Use of 2,4-Pyrimidinediamines For the Treatment of Atherosclerosis

ABSTRACT

Novel methods and compositions for the prevention and treatment of all forms of atherosclerosis with 2,4-pyrimidinediamine compounds are described. Also disclosed is the coating of prosthetic devices, such as stents, with the compounds of the invention for the prevention and/or treatment of restenosis.

I. INTRODUCTION

A. Field of the Invention

The present invention relates generally to the field of pharmaceuticaltreatment of atherosclerosis and its associated cardiovascular risk.

B. Background of the Invention

Cardiovascular disease, principally heart disease and stroke, killsapproximately one million Americans each year, making it the number onekiller in the United States. Elevated cholesterol levels in the bloodhave long been recognized as a risk factor and precursor for a widerange of health problems. Cardiovascular disease includes conditionsthat lead to narrowing or blockage of the heart, arteries, and veins.Atherosclerosis, often described as a hardening of the arteries, occurswhen the normal lining of the arteries deteriorates, the walls ofarteries thicken, and deposits of fat and plaque build up within thearteries, causing narrowing (or even blockage). Hypertension, or highblood pressure, results from narrowing of vessels due to similardeposits, which reduces the blood supply to all areas of the body, andcauses the heart to work harder to pump the same amount of blood.Inadequate oxygen flow to the brain causes stroke.

Environmental pollution, daily stress, and lifestyle behaviors can allcontribute to cardiovascular disease, as do a number of health-relatedbehaviors, including tobacco use, lack of physical activity, and poornutrition. Traditional treatment approaches include medication andsurgery, and many scientific studies show a positive effect from changesin diet and lifestyle. Thus, optimal treatment regimens can be complex.

Cardiovascular disease is the leading killer in the developed world,with U.S., deaths from heart disease and stroke accounting for 35% ofannual mortality. Cholesterol-lowering drugs are one of the mostsuccessful therapies in the world, generating over $27B in 2005 alone.While it is clear that lowering “bad” cholesterol (LDL, low-densitylipoproteins) can help prevent a host of serious cardiovascular eventsand raising “good” cholesterol levels (HDL, high-density lipoproteins)correlates with improved cardiac health, cholesterol levels alone arenot the only important factor determining cardiovascular risk. Thus, itis important to understand the links between high cholesterol, increasedbuild-up of fatty deposits (plaque) in the arteries, and heart disease,so that treatments can be optimized to specific patients.

A connection between mast cells and the pathogenesis of atherosclerosiswas first suggested in 1953 (Constantinides, Science 117: 505-6 (1953);Cairns et al., Science 120: 31-2 (1954)). Subsequent research hassupported this proposition (see Kovanen, Immunol. rev. 217:105-122(2007), incorporated herein by reference). For example, the number ofactivated mast cells in atherosclerotic plaques is especially high inthe shoulder regions prone to plaque rupture as compared to normalintima. Further, the number of plaque erosions and the proportion ofmast cells associated with erosions increases markedly as the diseasebecomes more severe. A significant mechanism leading to plaque ruptureis the increased degradation of extracellular and pericellular matrixcomponents in the fibrous cap. Activated mast cells secrete proteases,such as tryptase and chymase, that inactivate HDL and enhancedegradation of the extracellular matrix via activation of matrixmetalloproteinases (MMPs). The heparin proteoglycan component of theexocytosed granules bind apolipoprotein (apo)B-100 of LDL particles andlead to uptake of the LDL by macrophages and foam cells and ultimatelyto deposition of fatty streaks in the vascular plaque. Histaminereleased by activated mast cells also triggers coronary spasm, which canlead to plaque rupture and erosion. Thus pharmaceutical interventionaimed at inhibiting mast cell activation and subsequent degranulation isexpected to inhibit both the development and progression ofatherosclerosis.

A key step in mast cell activation is the cross-linking of Fc receptors,such as the high affinity receptor for IgE (FcεRI) and/or the highaffinity receptor for IgG (FcyRI). Such cross-linking activates asignaling cascade in mast and other immune cells that results in therelease of chemical mediators responsible for numerous adverse events.For example, such cross-linking leads to the release of preformedmediators, such as histamine and proteases, from storage sites ingranules via degranulation. It also leads to the synthesis and releaseof other mediators, including growth factors, various cytokines andplatelet-activating factors (PAPs), that play important roles in thedevelopment and progression of atherosclerosis. The signaling cascade(s)activated by cross-linking Fc receptors such as FcεRI and/or FcyRIcomprises an array of cellular proteins (see FIG. 1). Among the mostimportant intracellular signal propagators are the tyrosine kinases.And, an important tyrosine kinase involved in the signal transductionpathways associated with crosslinking the FcεRI and/or FcyRI receptors,as well as other signal transduction cascades, is Syk kinase (see Valentet al., 2002, Inti. J. Hematol. 75(4):257-362 for review).

Second, platelets play a pivotal role in the late stage ofatherosclerosis, during plaque rupture and thrombus formation. Inparticular, platelet P-selectin has been demonstrated to play a criticalrole in the development of atherosclerosis (Huo et al., Nat Med. 9:61-67(2003); Burger et al., Blood 101: 2661-2666 (2003)). CD62P participatesin the early steps of leukocyte recruitment and mediates interactions ofplatelets and leukocytes with the damaged vessel wall through multiplemechanisms. P-selectin (CD62P) is constitutively expressed and stored inthe α-granules of platelets and translocated rapidly to the cell surfacein response to several inflammatory stimuli. Activation anddegranulation by platelets is also mediated by the Syk pathway.

As the mediators released as a result of FcεRI and FcyRI receptorcross-linking in mast cells and platelets are responsible for, or playimportant roles in, the development and progression of atherosclerosis,the availability of compounds capable of inhibiting the signalingcascade(s) responsible for their release would be highly desirable.

II. SUMMARY OF THE INVENTION

Novel methods and compositions for the prevention and treatment of allforms of atherosclerosis with 2,4 pyrimidinediamine compounds aredescribed. Also disclosed is the coating of prosthetic devices, such asstents, with the compounds of the invention for the prevention and/ortreatment of restenosis.

One aspect of the invention provides methods of treating atherosclerosisor regressing or decreasing formation of arterial atheroscleroticlesions, said method comprising administering to a mammal havingatherosclerosis an effective amount of a Syk kinase inhibitor.

Another aspect of the invention provides methods of treatingatherosclerosis or regressing or decreasing formation of arterialatherosclerotic lesions, said method comprising administering to amammal having atherosclerosis an effective amount of a compound ofstructural formula I:

wherein:

-   -   L¹ and L² are each, independently of one another, selected from        the group consisting of a direct bond and a linker;    -   R² is selected from the group consisting of C₁₋₆ alkyl        optionally substituted with one or more of the same or different        R⁸ groups, C₃₋₈ cycloalkyl optionally substituted with one or        more of the same or different R⁸ groups, cyclohexyl optionally        substituted with one or more of the same or different R⁸ groups,        3-8 membered cycloheteroalkyl optionally substituted with one or        more of the same or different R⁸ groups, C₅₋₁₅ aryl optionally        substituted with one or more of the same or different R⁸ groups,        phenyl optionally substituted with one or more of the same or        different R⁸ groups and 5-15 membered heteroaryl optionally        substituted with one or more of the same or different R⁸ groups;    -   R⁴ is selected from the group consisting of hydrogen, C₁₋₆ alkyl        optionally substituted with one or more of the same or different        R⁸ groups, C₃₋₈ cycloalkyl optionally substituted with one or        more of the same or different R⁸ groups, 3-8 membered        cycloheteroalkyl optionally substituted with one or more of the        same or different R⁸ groups, C₅₋₁₅ aryl optionally substituted        with one or more of the same or different R⁸ groups, and 5-15        membered heteroaryl optionally substituted with one or more of        the same or different R⁸ groups;    -   R⁵ is selected from the group consisting of R⁶, C₁₋₆ alkyl        optionally substituted with one or more of the same or different        R⁸ groups; each R⁶ is independently selected from the group        consisting of hydrogen, an electronegative group, —OR^(d),        —SR^(d), C₁₋₃ haloalkyloxy, C₁₋₃ perhaloalkyloxy, —NR^(c)R^(c),        halogen, C₁₋₃ haloalkyl, C₁₋₃ perhaloalkyl, —CF₃, —CH₂CF₃,        —CF₂CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂, —N₃, —S(O)R^(d),        —S(O)₂R^(d), —S(O)₂OR^(d), —S(O)NR^(c)R^(c); —S(O)₂NR^(c)R^(c),        —OS(O)R^(d), —OS(O)₂R^(c), —OS(O)₂OR^(d), —OS(O)NR^(c)R^(c),        —OS(O)₂NR^(c)R^(c), —C(O)R^(d), —C(O)OR^(d), —C(O)NR^(c)R^(c),        —C(NH)NR^(c)R^(c), —OC(O)R^(d), —SC(O)R^(d), —OC(O)OR^(d),        —SC(O)OR^(d), —OC(O)NR^(c)R^(c), —SC(O)NR^(c)R^(c),        —OC(NH)NR^(c)R^(c), —SC(NH)NR^(c)R^(c), —[NHC(O)]_(n)R^(d)—,        —[NHC(O)]_(n)OR^(d), —[NHC(O)]_(n)NR^(c)R^(c) and        —[NHC(NH)]_(n)NR^(c)R^(c), C₅₋₁₀ aryl optionally substituted        with one or more of the same or different R⁸ groups, C₆₋₁₆        arylalkyl optionally substituted with one or more of the same or        different R⁸ groups, 5-10 membered heteroaryl optionally        substituted with one or more of the same or different R⁸ groups        and 6-16 membered heteroarylalkyl optionally substituted with        one or more of the same or different R⁸ groups;    -   R⁸ is selected from the group consisting of R^(e), R^(b), R^(e)        substituted with one or more of the same or different R^(a) or        R^(b), —OR^(a) substituted with one or more of the same or        different R^(a) or R^(b), —B(OR^(a))₂, —B(NR^(c)R^(c))₂,        —(CH₂)_(m)—R^(b), —(CHR^(a))_(m)—R^(b), —O—(CH₂)_(m)—R^(b),        —S(CH₂)_(m)—R^(b), —O—CHR^(a)R^(b), —O—CR^(a)(R^(a))₂,        —O—(CHR^(a))_(m)—R^(b), —O—(CH₂)_(m)—CH[(CH₂)_(m)R^(b)]R^(b),        —S—(CHR^(a))_(m)—R^(b); —C(O)NH—(CH₂)_(m)—R^(b),        —C(O)NH—(CHR^(a))_(m)—R^(b), —O(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),        —S—(CH₂)_(m)—R^(b), —C(O)NH—(CH₂)_(m)R^(b),        —O—(CHR^(a))_(m)—C(O)NH—(CHR.s-up.a)_(m)-R^(b),        —S—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b),        —NH—(CH₂)_(m)—R^(b), —NH—(CHR^(a))_(m)—R^(b),        —NH[(CH₂)_(m)R^(b)], —N[(CH₂)_(m)R^(b)]₂,        —NH—C(O)—NH—(CH₂)_(m)—R^(b), —NH—C(O)—(CH₂)_(m)—CHR^(b)R^(b) and        —NH—(CH₂)_(m)—C(O)—NH—(CH₂)_(m)—R^(b);    -   each R^(a) is independently selected from the group consisting        of hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₄₋₁₁ cycloalkylalkyl,        C₅₋₁₀ aryl, C₆₋₁₆ arylalkyl, 2-6 membered heteroalkyl, 3-8        membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl,        5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;    -   each R^(b) is independently selected from the group consisting        of ═O, —OR^(d), (C1-C3) haloalkyloxy, —OCF₃, ═S, —SR^(d),        ═NR^(d), ═NOR^(d), —NR^(c)R^(c), halogen, —CF₃, —CN, —NC, —OCN,        —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(d), —S(O)₂R^(d),        —S(O)₂OR^(d), —S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(d),        —OS(O)₂R^(d), —OS(O)₂OR^(d), —OS(O)₂NR^(c)R^(c), —C(O)R^(d),        —C(O)OR^(d), —C(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c),        —C(NR^(a))NR^(c)R^(c), —C(NOH)R^(a), —C(NOH)NR^(c)R^(c),        —OC(O)R^(d), —OC(O)OR^(d), —OC(O)NR^(c)R^(c),        —OC(NH)NR^(c)R^(c), —OC(NR^(a))NR^(c)R^(c), —[NHC(O)]_(n)R^(d),        —[NR^(a)C(O)]_(n)R^(d), —[NHC(O)]_(n)OR^(d),        —[NR^(a)C(O)]_(n)OR^(d), —[NHC(O)]_(n)NR^(c)R^(c),        —[NR^(a)C(O)]_(n)NR^(c)R^(c), —[NHC(NH)]_(n)NR^(c)R^(c) and        —[NR^(a)C(NR^(a))]_(n)NR^(c)R^(c);    -   each R^(c) is independently a protecting group or R^(a), or,        alternatively, each R^(c) is taken together with the nitrogen        atom to which it is bonded to form a 5 to 8-membered        cycloheteroalkyl or heteroaryl which may optionally include one        or more of the same or different additional heteroatoms and        which may optionally be substituted with one or more of the same        or different R^(a) or R^(b) groups;    -   each R^(d) is independently a protecting group or R^(a);    -   each R^(e) is independently selected from the group consisting        of C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₄₋₁₁ cycloalkylalkyl, C₆₋₁₀        aryl, C₆₋₁₆ arylalkyl, 2-6 membered heteroalkyl, 3-8 membered        cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10        membered heteroaryl and 6-16 membered heteroarylalkyl;    -   each m is independently an integer from 1 to 3; and    -   each n is independently an integer from 0 to 3.

Yet another aspect of the invention provides methods of treatingatherosclerosis or regressing or decreasing formation of arterialatherosclerotic lesions, said method comprising administering to amammal having atherosclerosis an effective amount of a compound offormula II:

wherein:

-   -   Y is selected from CH₂, NR²⁴, O, S, S(O) and S(O)₂;    -   Z¹ and Z² each, independently of one another, are selected from        CH and N;    -   R² is selected from (C1-C6) alkyl optionally substituted with        one or more of the same or different R⁸ groups, (C3-C8)        cycloalkyl optionally substituted with one or more of the same        or different R⁸ groups, 3-8 membered cycloheteroalkyl optionally        substituted with one or more of the same or different R⁸ groups,        (C6-C14) aryl optionally substituted with one or more of the        same or different R⁸ groups, and 5-15 membered heteroaryl        optionally substituted with one or more of the same or different        R⁸ groups;    -   R⁵ is selected from halo, cyano, nitro, and trihalomethyl;    -   R⁸ is selected from R^(a), R^(b), R^(a) substituted with one or        more of the same or different R^(a) or R^(b), —OR^(a)        substituted with one or more of the same or different R^(a) or        R^(b), —B(OR^(a))₂, —B(NR^(c)R^(c))₂, —(CH₂)_(m)—R^(b),        —(CHR^(a))_(m)—R^(b), —O—(CH₂)_(m)—R^(b), —S—(CH2)_(m)—R^(b),        —O—CHR^(a)R^(b), —O—CR^(a)(R^(b))₂, —O—(CHR^(a))_(m)—R^(b),        —O—(CH₂)_(m)—CH[(CH₂)_(m)R^(b)]R^(b), —S—(CHR^(a))_(m)—R^(b),        —C(O)NH—(CH₂)_(m)—R^(b), —C(O)NH—(CHR^(a))_(m)—Rb,        —O—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b)        —S—(CH₂)_(m)—C(O)NH—(CH2)_(m)—R^(b),        —O—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b),        —S—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b),        —NH—(CH₂)_(m)—R^(b), —NH—(CHR^(a))_(m)—R^(b),        —NH[(CH₂)_(m)R^(b)], —N[(CH₂)_(m)R^(b)]₂,        —NH—C(O)—NH—(CH₂)_(m)—R^(b), —NH—C(O)—(CH₂)_(m)—CHR^(b)R^(b) and        —NH—(CH₂)_(m)—C(O)—NH—(CH₂)_(m)—R^(b);    -   R¹⁷ is selected from hydrogen, halogen, and lower alkyl or,        alternatively, R¹⁷ may be taken together with R¹⁸ to form an oxo        (═O) group or, together with the carbon atom to which they are        attached, a spirocycle containing from 3 to 7 carbon atoms;    -   R¹⁸ is selected from hydrogen, halogen, and lower alkyl or,        alternatively, R¹⁸ may be taken together with R¹⁷ to form an oxo        (═O) group or, together with the carbon atom to which they are        attached, a spirocycle containing from 3 to 7 carbon atoms;    -   R¹⁹ is selected from hydrogen and lower alkyl or, alternatively,        R¹⁹ may be taken together with R²⁰ to form an oxo (═O) group or,        together with the carbon atom to which they are attached, a        spirocycle containing from 3 to 7 carbon atoms;    -   R²⁰ is selected from hydrogen and lower alkyl or, alternatively,        R²⁰ may be taken together with R¹⁹ to form an oxo (═O) group or,        together with the carbon atom to which they are attached, a        spirocycle containing from 3 to 7 carbon atoms;    -   each R^(a) is, independently of the others, selected from        hydrogen, lower alkyl, lower cycloalkyl, (C4-C11)        cycloalkylalkyl, (C6-C10) aryl, (C7-C16) arylalkyl, 2-6 membered        heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered        cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16        membered heteroarylalkyl;    -   each R^(b) is independently selected from ═O, —OR^(a), (C1-C3)        haloalkyloxy, ═S, —SR^(a), ═NR^(a), ═NOR^(a), —NR^(c)R^(c),        halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃,        —S(O)R^(a), —S(O)₂R^(a), —S(O)₂OR^(a), —S(O)NR^(c)R^(c),        —S(O)₂NR^(c)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)₂OR^(a),        —OS(O)₂NR^(c)R^(c), —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(c)R^(c),        —C(NH)NR^(c)R^(c), —C(NR^(a))NR^(c)Rc, —C(NOH)R^(a),        —C(NOH)NR^(c)R^(c), —OC(O)R^(a), —OC(O)OR^(a),        —OC(O)NR^(c)R^(c), —OC(NH)NR^(c)R^(c), —OC(NR^(a))NR^(c)R^(c),        —[NHC(O)]_(n)R^(a), —[NR^(a)C(O)]_(n)R^(a), —[NHC(O)]_(n)OR^(a),        —[NR^(a)C(O)]_(n)OR^(a), —[NHC(O)]_(n)NR^(c)R^(c),        —[NR^(a)C(O)]_(n)NR^(c)R^(c), —[NHC(NH)]_(n)NR^(c)R^(c) and        —[NR^(a)C(NR^(a))]_(n)NR^(c)R^(c);    -   each R^(c) is, independently of the others, selected from a        protecting group and R^(a), or, alternatively, the two R^(c)        bonded to the same nitrogen atom are taken together with that        nitrogen atom to form a 5 to 8-membered cycloheteroalkyl or        heteroaryl which may optionally include one or more of the same        or different additional heteroatoms and which may optionally be        substituted with one or more of the same or different R^(a)        groups;    -   R²¹, R²² and R²³ are each, independently of one another,        selected from hydrogen and a progroup R^(P);    -   R^(P) has the formula —(CR^(d)R^(d))_(y)-A-R³, where y is an        integer ranging from 1 to 3; A is O or S; each R^(d) is,        independently of the others, selected from hydrogen, optionally        substituted lower alkyl, optionally substituted (C6-C14) aryl        and optionally substituted (C7-C20) arylalkyl; where the        optional substituents are, independently of one another,        selected from hydroxyl, lower alkoxy, (C6-C14) aryloxy, lower        alkoxyalkyl and halogen, or, alternatively, two R^(d) bonded to        the same carbon atom, taken together with the carbon atom to        which they are bonded, form a cycloalkyl group containing from 3        to 8 carbon atoms;    -   R³ comprises, together with the heteroatom, A, to which it is        bonded, an alcohol, an ether, a thioether, a silyl ether, a        silyl thioether, an ester, a thioester, an amide, a carbonate, a        thiocarbonate, a carbamate, a thiocarbamate, a urea, a        phosphate, a phosphate salt or a phosphate ester;    -   each m is, independently of the others, an integer from 1 to 3;        and    -   each n is, independently of the others, an integer from 0 to 3,        with the proviso that at least one of R²¹, R²², and R²³ is        R^(P).

III. BRIEF DESCRIPTION OF THE DRAWINGS

The skilled artisan will understand that the drawings, described below,are for illustration purposes only. The drawings are not intended tolimit the scope of the present teaching in any way.

FIG. 1 provides a cartoon illustrating the FcεR1 signal transductioncascade leading to degranulation of mast cells.

FIG. 2 provides the results of collagen, ADP and PMA-induced surfaceexpression of CD62P by platelets treated with a 2,4 pyrimidinediamine ofthe invention or wortmannin.

IV. DETAILED DESCRIPTION A. Overview

The invention encompasses novel methods and compositions for theprevention and treatment of all forms of atherosclerosis with 2,4pyrimidinediamine compounds are described. Also disclosed is the coatingof prosthetic devices, such as stents, with the compounds of theinvention for the prevention and/or treatment of restenosis.

B. Definitions

As used herein, the following definitions shall apply unless otherwiseindicated.

“Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groupshaving from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms.This term includes, by way of example, linear and branched hydrocarbylgroups such as methyl (CH₃—), ethyl (CH₃CH₂—), n-propyl (CH₃CH₂CH₂—),isopropyl ((CH₃)₂CH—), n-butyl (CH₃CH₂CH₂CH₂—), isobutyl ((CH₃)₂CHCH₂—),sec-butyl ((CH₃)(CH₃CH₂)CH—), t-butyl ((CH₃)₃C—), n-pentyl(CH₃CH₂CH₂CH₂CH₂—), and neopentyl ((CH₃)₃CCH₂—).

“Substituted alkyl” refers to an alkyl group having from 1 to 5hydrogens replaced with substituents selected from the group consistingof alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino,substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,aminosulfonyloxy, sulfonylamino, aminosulfonylamino, amidino, aryl,substituted aryl, aryloxy, substituted aryloxy, arylthio, substitutedarylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxylester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy,substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio,cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substitutedcycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio,guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substitutedheteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio,substituted heteroarylthio, heterocyclic, substituted heterocyclic,heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio,substituted heterocyclylthio, nitro, SO₃H, sulfonyl, sulfonyloxy,thioacyl, thiol, alkylthio, and substituted alkylthio, wherein saidsubstituents are defined herein. In some embodiments, the alkyl has 1 to3 of the aforementioned groups. In other embodiments, the alkyl has 1 to2 of the aforementioned groups.

“Alkylene” refers to divalent saturated aliphatic hydrocarbyl groupspreferably having from 1 to 6 and more preferably 1 to 3 carbon atomsthat are either straight-chained or branched. This term is exemplifiedby groups such as methylene (—CH₂—), ethylene (—CH₂CH₂—), n-propylene(—CH₂CH₂CH₂—), iso-propylene (—CH₂CH(CH₃)—) or (—CH(CH₃)CH₂—), and thelike.

“Substituted alkylene” refers to an alkylene group having from 1 to 3hydrogens replaced with substituents selected from the group consistingof alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl,acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aryl,substituted aryl, aryloxy, substituted aryloxy, cyano, halogen,hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, substitutedcycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, and oxo wherein said substituents are definedherein. In some embodiments, the alkylene has 1 to 2 of theaforementioned groups. It is to be noted that when the alkylene issubstituted by an oxo group, 2 hydrogens attached to the same carbon ofthe alkylene group are replaced by “═O”.

“Alkoxy” refers to the groups —O-alkyl, —O-alkenyl, and —O-alkynyl,wherein alkyl, alkenyl and alkynyl are as defined herein.

“Substituted alkoxy” refers to the groups —O-(substituted alkyl),—O-(substituted alkenyl), and —O-(substituted alkynyl), whereinsubstituted alkyl, substituted alkenyl, and substituted alkynyl are asdefined herein.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)-cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—,cycloalkenyl-C(O)—, substituted cycloalkenyl-C(O)—, aryl-C(O)—,substituted aryl-C(O)—, heteroaryl-C(O)—, substituted heteroaryl-C(O)—,heterocyclic-C(O)—, and substituted heterocyclic-C(O)—, wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein. Acyl includes the “acetyl” group CH₃C(O)—.

“Acylamino” refers to the groups —NR²⁰C(O)alkyl, —NR²⁰C(O)substitutedalkyl, —NR²⁰C(O)cycloalkyl, —NR²⁰C(O)substituted cycloalkyl,—NR²⁰C(O)cycloalkenyl, —NR²⁰C(O)substituted cycloalkenyl,—NR²⁰C(O)alkenyl, —NR²⁰C(O)substituted alkenyl, —NR²⁰C(O)alkynyl,—NR²⁰C(O)substituted alkynyl, —NR²⁰C(O)aryl, —NR²⁰C(O)substituted aryl,—NR²⁰C(O)heteroaryl, —NR²⁰C(O)substituted heteroaryl,—NR²⁰C(O)heterocyclic, and —NR²⁰C(O)substituted heterocyclic, whereinR²⁰ is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“Acyloxy” refers to the groups alkyl-C(O)O—, substituted alkyl-C(O)O—,alkenyl-C(O)O—, substituted alkenyl-C(O)O—, alkynyl-C(O)O—, substitutedalkynyl-C(O)O—, aryl-C(O)O—, substituted aryl-C(O)O—, cycloalkyl-C(O)O—,substituted cycloalkyl-C(O)O—, cycloalkenyl-C(O)O—, substitutedcycloalkenyl-C(O)O—, heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—,heterocyclic-C(O)O—, and substituted heterocyclic-C(O)O—, wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein.

“Amino” refers to the group —NH₂.

“Substituted amino” refers to the group —NR²¹R²², wherein R²¹ and R²²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, where one of R²¹ andR²² is sulfonyl, and wherein R²¹ and R²² are optionally joined togetherwith the nitrogen bound thereto to form a heterocyclic or substitutedheterocyclic group, provided that R²¹ and R²² are not both hydrogen, andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, sulfonyl,substituted heteroaryl, heterocyclic, and substituted heterocyclic areas defined herein. When R²¹ is hydrogen and R²² is alkyl, thesubstituted amino group is sometimes referred to herein as “alkylamino.”When R²¹ and R²² are alkyl, the substituted amino group is sometimesreferred to herein as “dialkylamino.” When referring to amonosubstituted amino, it is meant that either R²¹ or R²² is hydrogen,but not both. When referring to a disubstituted amino, it is meant thatneither R²¹ nor R²² is hydrogen.

“Aminocarbonyl” refers to the group —C(O)NR²¹R²², wherein R²¹ and R²²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R²¹ andR²² are optionally joined together with the nitrogen bound thereto toform a heterocyclic or substituted heterocyclic group, and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic areas defined herein.

“Aminothiocarbonyl” refers to the group —C(S)NR²¹R²², wherein R²¹ andR²² independently are selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic andwhere R²¹ and R²² are optionally joined together with the nitrogen boundthereto to form a heterocyclic or substituted heterocyclic group, andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic areas defined herein.

“Aminocarbonylamino” refers to the group —NR²⁰C(O)NR²¹R²² wherein R²⁰ ishydrogen or alkyl and R²¹ and R²² independently are selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic and where R²¹ and R²² are optionally joinedtogether with the nitrogen bound thereto to form a heterocyclic orsubstituted heterocyclic group, and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Aminothiocarbonylamino” refers to the group —NR²⁰C(S)NR²¹R²², whereinR²⁰ is hydrogen or alkyl and R²¹ and R²² independently are selected fromthe group consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic and where R²¹ and R²² are optionally joinedtogether with the nitrogen bound thereto to form a heterocyclic orsubstituted heterocyclic group, and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Aminocarbonyloxy” refers to the group —O—C(O)NR²¹R²², wherein R²¹ andR²² independently are selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic andwhere R²¹ and R²² are optionally joined together with the nitrogen boundthereto to form a heterocyclic or substituted heterocyclic group, andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic are asdefined herein.

“Aminosulfonyl” refers to the group —SO₂NR²¹R²², wherein R²¹ and R²²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic and where R²¹ and R²²are optionally joined together with the nitrogen bound thereto to form aheterocyclic or substituted heterocyclic group and alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminosulfonyloxy” refers to the group —O—SO₂NR²¹R²², wherein R²¹ andR²² independently are selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic; R²¹and R²² are optionally joined together with the nitrogen bound theretoto form a heterocyclic or substituted heterocyclic group; and alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein.

“Aminosulfonylamino” refers to the group —NR²⁰—SO₂NR²¹R²², wherein R²⁰is hydrogen or alkyl and R²¹ and R²² independently are selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic and where R²¹ and R²² are optionally joinedtogether with the nitrogen bound thereto to form a heterocyclic orsubstituted heterocyclic group, and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Sulfonylamino” refers to the group —NR²¹SO₂R²², wherein R²¹ and R²²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R²¹ andR²² are optionally joined together with the atoms bound thereto to forma heterocyclic or substituted heterocyclic group, and wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein.

“Amidino” refers to the group —C(═NR³⁰)NR³¹R³², wherein R³¹ and R³²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R³¹ andR³² are optionally joined together with the nitrogen bound thereto toform a heterocyclic or substituted heterocyclic group. R³⁰ is selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkynyl, substituted cycloalkynyl, aryl, substituted aryl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, nitro, nitroso, hydroxy, alkoxy, cyano, acyl,—SO₂-alkyl and —SO₂-substituted alkyl, wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkynyl, substituted cycloalkynyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, nitro, nitroso, hydroxy, alkoxy, and cyano are as definedherein.

“Aryl” refers to a monovalent aromatic carbocyclic group of from 6 to 14carbon atoms having a single ring (e.g., phenyl) or multiple condensedrings (e.g., naphthyl or anthryl) which condensed rings may or may notbe aromatic provided that the point of attachment is through an atom ofthe aromatic aryl group. As used herein multiple rings refers to fused,bridged or spiro ring systems consisting of 2, 3 or 4 rings. Forexample, 1, 2,3,4-tetrahydronaphthalen-5-yl, 9H-fluoren-2-yl, and thelike. Preferred aryl groups include phenyl and naphthyl.

“Substituted aryl” refers to aryl groups having 1 to 5 hydrogensreplaced with substituents independently selected from the groupconsisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl,acylamino, acyloxy, amino, substituted amino, aminocarbonyl,aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino,amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio,substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino,(carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl,cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substitutedcycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy,substituted cycloalkenyloxy, cycloalkenylthio, substitutedcycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy,heteroaryl, substituted heteroaryl, heteroaryloxy, substitutedheteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic,substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy,heterocyclylthio, substituted heterocyclylthio, nitro, SO₃H, sulfonyl,sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio,wherein said substituents are as defined herein. In some embodiments,the aryl has 1 to 3 of the aforementioned groups. In other embodiments,the aryl has 1 to 2 of the aforementioned groups. In some embodiments,substituted aryl includes compounds containing oxo substituent in thenon-aromatic ring fused to the aryl group. For example,1-oxo-indan-4-yl, wherein the point of attachment is through the phenylring.

“Aryloxy” refers to the group —O-aryl, wherein aryl is as definedherein, including, by way of example, phenoxy, naphthoxy, and the like.

“Substituted aryloxy” refers to the group —O-(substituted aryl), whereinsubstituted aryl is as defined herein.

“Arylthio” refers to the group —S-aryl, wherein aryl is as definedherein. In other embodiments, sulfur may be oxidized to —S(O)— or —SO₂—moieties. The sulfoxide may exist as one or more stereoisomers.

“Substituted arylthio” refers to the group —S-(substituted aryl),wherein substituted aryl is as defined herein. In other embodiments,sulfur may be oxidized to —S(O)— or —SO₂— moieties. The sulfoxide mayexist as one or more stereoisomers.

“Alkenyl” refers to straight chain or branched hydrocarbyl groups havingfrom 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and havingat least 1 and preferably from 1 to 2 sites of vinyl (>C═C<)unsaturation. Such groups are exemplified by vinyl, allyl, andbut-3-en-1-yl. Included within this term are the cis and trans isomersor mixtures of these isomers.

“Substituted alkenyl” refers to alkenyl groups having from 1 to 3substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, acyloxy, amino, substituted amino,aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl,carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano,cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substitutedcycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl,substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,cycloalkenylthio, substituted cycloalkenylthio, guanidino, substitutedguanidino, halo, hydroxy, heteroaryl, substituted heteroaryl,heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substitutedheteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,substituted heterocyclyloxy, heterocyclylthio, substitutedheterocyclylthio, nitro, SO₃H, sulfonyl, sulfonyloxy, thioacyl, thiol,alkylthio, and substituted alkylthio, wherein said substituents are asdefined herein and with the proviso that any hydroxy substitution is notattached to a vinyl (unsaturated) carbon atom. In some embodiments, thealkenyl has 1 to 2 of the aforementioned groups.

“Alkynyl” refers to straight or branched monovalent hydrocarbyl groupshaving from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms andhaving at least 1 and preferably from 1 to 2 sites of acetylenic —C═C—unsaturation. Examples of such alkynyl groups include acetylenyl(—C≡CH), and propargyl (—CH₂C≡CH).

“Substituted alkynyl” refers to alkynyl groups having from 1 to 3substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, acyloxy, amino, substituted amino,aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl,carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano,cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substitutedcycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl,substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,cycloalkenylthio, substituted cycloalkenylthio, guanidino, substitutedguanidino, halo, hydroxy, heteroaryl, substituted heteroaryl,heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substitutedheteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,substituted heterocyclyloxy, heterocyclylthio, substitutedheterocyclylthio, nitro, SO₃H, sulfonyl, sulfonyloxy, thioacyl, thiol,alkylthio, and substituted alkylthio, wherein said substituents are asdefined herein and with the proviso that any hydroxy or thiolsubstitution is not attached to an acetylenic carbon atom. In someembodiments, the alkynyl has 1 to 2 of the aforementioned groups.

“Alkynyloxy” refers to the group —O-alkynyl, wherein alkynyl is asdefined herein. Alkynyloxy includes, by way of example, ethynyloxy,propynyloxy, and the like.

“Carboxyl” or “carboxy” refers to —COOH or salts thereof.

“Carboxyl ester” or “carboxy ester” refers to the groups —C(O)O-alkyl,—C(O)O-substituted alkyl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl,—C(O)O-alkynyl, —C(O)O-substituted alkynyl, —C(O)O-aryl,—C(O)O-substituted aryl, —C(O)O-cycloalkyl, —C(O)O-substitutedcycloalkyl, —C(O)O-cycloalkenyl, —C(O)O-substituted cycloalkenyl,—C(O)O-heteroaryl, —C(O)O-substituted heteroaryl, —C(O)O-heterocyclic,and —C(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“(Carboxyl ester)amino” refers to the groups —NR—C(O)O-alkyl,—NR—C(O)O-substituted alkyl, —NR—C(O)O-alkenyl, —NR—C(O)O-substitutedalkenyl, —NR—C(O)O-alkynyl, —NR—C(O)O-substituted alkynyl,—NR—C(O)O-aryl, —NR—C(O)O-substituted aryl, —NR—C(O)O-cycloalkyl,—NR—C(O)O-substituted cycloalkyl, —NR—C(O)O-cycloalkenyl,—NR—C(O)O-substituted cycloalkenyl, —NR—C(O)O-heteroaryl,—NR—C(O)O-substituted heteroaryl, —NR—C(O)O-heterocyclic, and—NR—C(O)O-substituted heterocyclic, wherein R is alkyl or hydrogen andalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic areas defined herein.

“(Carboxyl ester)oxy” refers to the groups —O—C(O)O-alkyl,—O—C(O)O-substituted alkyl, —O—C(O)O-alkenyl, —O—C(O)O-substitutedalkenyl, —O—C(O)O-alkynyl, —O—C(O)O-substituted alkynyl, —O—C(O)O-aryl,—O—C(O)O-substituted aryl, —O—C(O)O-cycloalkyl, —O—C(O)O-substitutedcycloalkyl, —O—C(O)O-cycloalkenyl, —O—C(O)O-substituted cycloalkenyl,—O—C(O)O-heteroaryl, —O—C(O)O-substituted heteroaryl,—O—C(O)O-heterocyclic, and —O—C(O)O-substituted heterocyclic, whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic areas defined herein.

“Cyano” or “nitrile” refers to the group —CN.

“Cycloalkyl” refers to cyclic alkyl groups of from 3 to 13 carbon atomshaving single or multiple cyclic rings including fused, bridged, andspiro ring systems. Examples of cycloalkyl groups include adamantyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like. One ormore rings fused to the cycloalkyl group can be aromatic, provided thatthe point of attachment is through the non-aromatic ring, e.g.9H-fluoren-9-yl, 1, 2,3,4-tetrahydronaphthalen-2-yl, and the like.

“Cycloalkenyl” refers to non-aromatic cyclic alkyl groups of from 3 to10 carbon atoms having single or multiple rings and having at least onedouble bond and preferably from 1 to 2 double bonds.

“Cycloalkynyl” refers to non-aromatic cycloalkyl groups of from 7 to 12carbon atoms having single or multiple rings and having at least onetriple bond.

“Cycloalkylene” refers to divalent cycloalkyl groups, wherein cycloalkylis as defined herein.

“Substituted cycloalkylene” refers to cycloalkylene group having from 1to 3 hydrogens replaced with substituents selected from the groupconsisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aryl,substituted aryl, aryloxy, substituted aryloxy, cyano, halogen,hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, substitutedcycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, and oxo wherein said substituents are asdefined herein. In some embodiments, the alkylene has 1 to 2 of theaforementioned groups. It is to be noted that when the cycloalkylene issubstituted by an oxo group, 2 hydrogens attached to the same carbon ofthe cycloalkylene group are replaced by “═O”.

“Substituted cycloalkyl,” “substituted cycloalkenyl,” and “substitutedcycloalkynyl” refer to a cycloalkyl, cycloalkenyl, or cycloalkynyl grouphaving from 1 to 5 substituents selected from the group consisting ofoxo, thioxo, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl,acylamino, acyloxy, amino, substituted amino, aminocarbonyl,aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino,amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio,substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino,(carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl,cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substitutedcycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy,substituted cycloalkenyloxy, cycloalkenylthio, substitutedcycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy,heteroaryl, substituted heteroaryl, heteroaryloxy, substitutedheteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic,substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy,heterocyclylthio, substituted heterocyclylthio, nitro, SO₃H, sulfonyl,sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio,wherein said substituents are as defined herein, provides that anyhydroxy or thiol substitution is not attached to an unsaturated carbonatom. In some embodiments, the cycloalkyl or cycloalkenyl has 1 to 3 ofthe aforementioned groups.

“Cycloalkoxy” refers to —O-cycloalkyl.

“Substituted cycloalkoxy” refers to —O-(substituted cycloalkyl).

“Cycloalkylthio” refers to —S-cycloalkyl. In other embodiments, sulfurmay be oxidized to —S(O)— or —SO₂— moieties. The sulfoxide may exist asone or more stereoisomers.

“Substituted cycloalkylthio” refers to —S-(substituted cycloalkyl). Inother embodiments, sulfur may be oxidized to —S(O)—, or —SO₂— moieties.The sulfoxide may exist as one or more stereoisomers.

“Cycloalkenyloxy” refers to —O-cycloalkenyl.

“Substituted cycloalkenyloxy” refers to —O-(substituted cycloalkenyl).

“Cycloalkenylthio” refers to —S-cycloalkenyl. In other embodiments,sulfur may be oxidized to sulfinyl or sulfonyl moieties. The sulfoxidemay exist as one or more stereoisomers.

“Substituted cycloalkenylthio” refers to —S-(substituted cycloalkenyl).In other embodiments, sulfur may be oxidized to —S(O)— or —SO₂—moieties. The sulfoxide may exist as one or more stereoisomers.

“Guanidino” refers to the group —NHC(═NH)NH₂.

“Substituted guanidino” refers to the group —NR³³C(═NR³³)N(R³³)₂,wherein each R³³ independently is selected from the group consisting ofhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic; twoR groups attached to a common guanidino nitrogen atom are optionallyjoined together with the nitrogen bound thereto to form a heterocyclicor substituted heterocyclic group, provided that at least one R is nothydrogen; and said substituents are as defined herein.

“Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo and ispreferably fluoro or chloro.

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Heteroaryl” refers to an aromatic group of from 1 to 10 carbon atomsand 1 to 4 heteroatoms selected from the group consisting of oxygen,nitrogen, and sulfur within the ring. Such heteroaryl groups can have asingle ring (e.g., pyridinyl or furyl) or multiple condensed rings(e.g., indolizinyl or benzothienyl), wherein the condensed rings may ormay not be aromatic and/or contain a heteroatom, provided that the pointof attachment is through an atom of the aromatic group containing theheteroatom. In one embodiment, the nitrogen and/or sulfur ring atom(s)of the heteroaryl group are optionally oxidized to provide for theN-oxide (N→O), sulfinyl, or sulfonyl moieties. Preferred heteroarylsinclude pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.

“Substituted heteroaryl” refers to heteroaryl groups that aresubstituted with from 1 to 5 substituents selected from the groupconsisting of the same group of substituents defined for substitutedaryl. In some embodiments, the heteroaryl has 1 to 3 of theaforementioned groups. In other embodiments, the heteroaryl has 1 to 2of the aforementioned groups.

“Heteroaryloxy” refers to —O-heteroaryl.

“Substituted heteroaryloxy” refers to the group —O-(substitutedheteroaryl).

“Heteroarylthio” refers to the group —S-heteroaryl. In otherembodiments, sulfur may be oxidized to —S(O)— or —SO₂— moieties. Thesulfoxide may exist as one or more stereoisomers.

“Substituted heteroarylthio” refers to the group —S-(substitutedheteroaryl). In other embodiments, sulfur may be oxidized to —S(O)— or—SO₂— moieties. The sulfoxide may exist as one or more stereoisomers.

“Heterocycle,” “heterocyclic,” “heterocycloalkyl,” and “heterocyclyl”refer to a saturated or unsaturated group having a single ring ormultiple condensed rings, including fused bridged and spiro ringsystems, and having from 3 to 15 ring atoms, including 1 to 4 heteroatoms. These ring atoms are selected from the group consisting ofnitrogen, sulfur, or oxygen, wherein, in fused ring systems, one or moreof the rings can be cycloalkyl, aryl, or heteroaryl, provided that thepoint of attachment is through the non-aromatic ring. In one embodiment,the nitrogen and/or sulfur atom(s) of the heterocyclic group areoptionally oxidized to provide for the N-oxide, —S(O)—, or —SO₂—moieties.

“Substituted heterocyclic,” “substituted heterocycloalkyl,”and“substituted heterocyclyl” refer to heterocyclyl groups that aresubstituted with from 1 to 5 of the same substituents as defined forsubstituted cycloalkyl. In some embodiments, the heterocyclyl has 1 to 3of the aforementioned groups.

“Heterocyclyloxy” refers to the group —O-heterocycyl.

“Substituted heterocyclyloxy” refers to the group —O-(substitutedheterocycyl).

“Heterocyclylthio” refers to the group —S-heterocycyl. In otherembodiments, sulfur may be oxidized to —S(O)— or —SO₂— moieties. Thesulfoxide may exist as one or more stereoisomers.

“Substituted heterocyclylthio” refers to the group —S-(substitutedheterocycyl). In other embodiments, sulfur may be oxidized to —S(O)— or—SO₂— moieties. The sulfoxide may exist as one or more stereoisomers.

Examples of heterocycle and heteroaryls include, but are not limited to,azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine,pyridazine, indolizine, isoindole, indole, dihydroindole, indazole,purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2,3,4-tetrahydroisoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to asthiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine,tetrahydrofuranyl, and the like.

“Nitro” refers to the group —NO₂.

“Nitroso” refers to the group —NO.

“Oxo” refers to the atom (═O).

“Sulfonyl” refers to the group —SO₂-alkyl, —SO₂-substituted alkyl,—SO₂-alkenyl, —SO₂-substituted alkenyl, —SO₂-cycloalkyl,—SO₂-substituted cylcoalkyl, —SO₂-cycloalkenyl, —SO₂-substitutedcycloalkenyl, —SO₂-aryl, —SO₂-substituted aryl, —SO₂-heteroaryl,—SO₂-substituted heteroaryl, —SO₂-heterocyclic, and —SO₂-substitutedheterocyclic, wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic are as defined herein. Sulfonyl includes groups such asmethyl-SO₂—, phenyl-SO₂—, and 4-methylphenyl-SO₂—.

“Sulfonyloxy” refers to the group —OSO₂-alkyl, —OSO₂-substituted alkyl,—OSO₂-alkenyl, —OSO₂-substituted alkenyl, —OSO₂-cycloalkyl,—OSO₂-substituted cylcoalkyl, —OSO₂-cycloalkenyl, —OSO₂-substitutedcycloalkenyl, —OSO₂-aryl, —OSO₂-substituted aryl, —OSO₂-heteroaryl,—OSO₂-substituted heteroaryl, —OSO₂-heterocyclic, and —OSO₂-substitutedheterocyclic, wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic are as defined herein.

“Thioacyl” refers to the groups H—C(S)—, alkyl-C(S)—, substitutedalkyl-C(S)—, alkenyl-C(S)—, substituted alkenyl-C(S)—, alkynyl-C(S)—,substituted alkynyl-C(S)—, cycloalkyl-C(S)—, substitutedcycloalkyl-C(S)—, cycloalkenyl-C(S)—, substituted cycloalkenyl-C(S)—,aryl-C(S)—, substituted aryl-C(S)—, heteroaryl-C(S)—, substitutedheteroaryl-C(S)—, heterocyclic-C(S)—, and substitutedheterocyclic-C(S)—, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“Thiol” refers to the group —SH.

“Thioxo” refers to the group (═S).

“Alkylthio” refers to the group —S-alkyl, wherein alkyl is as definedherein. In other embodiments, sulfur may be oxidized to —S(O)—. Thesulfoxide may exist as one or more stereoisomers.

“Substituted alkylthio” refers to the group —S-(substituted alkyl),wherein substituted alkyl is as defined herein. In other embodiments,sulfur may be oxidized to —S(O)—. The sulfoxide may exist as one or morestereoisomers.

“Stereoisomer” and “stereoisomers” refer to compounds that differ in thechirality of one or more stereocenters. Stereoisomers includeenantiomers and diastereomers.

“Tautomer” refers to alternate forms of a molecule that differ in theposition of a proton, such as enol-keto and imine-enamine tautomers, orthe tautomeric forms of heteroaryl groups containing a —N═C(H)—NH— ringatom arrangement, such as pyrazoles, imidazoles, benzimidazoles,triazoles, and tetrazoles. A person of ordinary skill in the art wouldrecognize that other tautomeric ring atom arrangements are possible.

“Patient” refers to human and non-human animals, especially mammals.

“Pharmaceutically acceptable salt” refers to pharmaceutically acceptablesalts of a compound, which salts are derived from a variety of organicand inorganic counter ions well known in the art and include, by way ofexample only, sodium, potassium, calcium, magnesium, ammonium,tetraalkylammonium, and the like; and when the molecule contains a basicfunctionality, salts of organic or inorganic acids, such ashydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate,oxalate, and the like.

“Prodrug” refers to a derivative of an active 4-pyrimidineamine compound(drug) that may require a transformation under the conditions of use,such as within the body, to release the active 2,4-pyrimidinediaminedrug. Prodrugs are frequently, but not necessarily, pharmacologicallyinactive until converted into the active drug. Prodrugs are typicallyobtained by masking one or more functional groups in an active2,4-pyrimidinediamine drug believed to be in part required for activitywith a progroup (defined below) to form a promoiety which undergoes atransformation, such as cleavage, under the specified conditions of useto release the functional group, and hence the active2,4-pyrimidinediamine drug. The cleavage of the promoiety may proceedspontaneously, such as by way of a hydrolysis reaction, or it can becatalyzed or induced by another agent, such as an enzyme, light, an acidor base, or a change of or exposure to a physical or environmentalparameter, such as temperature. The agent can be endogenous to theconditions of use, such as an enzyme present in the cells to which theprodrug is administered or the acidic conditions of the stomach, or itcan be supplied exogenously.

“Progroup” refers to a type of protecting group that, when used to maska functional group within an active 2,4-pyrimidinediamine drug to form apromoiety, converts the drug into a prodrug. Progroups are typicallyattached to the functional group of the drug via bonds that arecleavable under specified conditions of use. Thus, a progroup is thatportion of a promoiety that cleaves to release the functional groupunder the specified conditions of use. As a specific example, an amidepromoiety of the formula —NH—C(O)CH₃ comprises the progroup —C(O)CH₃.

“Pharmaceutically effective amount” and “therapeutically effectiveamount” refer to an amount of a compound sufficient to treat a specifieddisorder or disease or one or more of its symptoms and/or to prevent theoccurrence of the disease or disorder. In reference to tumorigenicproliferative disorders, a pharmaceutically or therapeutically effectiveamount comprises an amount sufficient to, among other things, cause thetumor to shrink or decrease the growth rate of the tumor.

“Solvate” refers to a complex formed by combination of solvent moleculeswith molecules or ions of the solute. The solvent can be an organiccompound, an inorganic compound, or a mixture of both. Some examples ofsolvents include, but are not limited to, methanol,N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water.

“Linker” refers to a moiety that attaches the N2 and/or N4 substituentson the 2,4-pyrimidinediamine to their respective nitrogen atoms, whichmay be the same or different. The nature of the linkers can vary widely,and can include virtually any combination of atoms or groups useful forspacing one molecular moiety from another. For example, the linker maybe an acyclic hydrocarbon bridge (e.g, a saturated or unsaturatedalkyleno such as methano, ethano, etheno, propano, prop[1]eno, butano,but[1]eno, but[2]eno, buta[1,3]dieno, and the like), a monocyclic orpolycyclic hydrocarbon bridge (e.g., [1,2]benzeno, [2,3]naphthaleno, andthe like), a simple acyclic heteroatomic or heteroalkyldiyl bridge(e.g., —O—, —S—, —S—O—, —NH—, —PH—, —C(O)—, —C(O)NH—, —S(O)—, —S(O)₂—,—S(O)NH—, —S(O)₂NH—, —O—CH—, —CH₂—O—CH₂—, —O—CH═CH—CH₂—, and the like),a monocyclic or polycyclic heteroaryl bridge (e.g., [3,4]furano,pyridino, thiopheno, piperidino, piperazino, pyrazidino, pyrrolidino,and the like) or combinations of such bridges. The linkers may befurther substituted with one or more of the same or differentsubstituent groups. The nature of these substituent groups may varybroadly. Non-limiting examples of suitable substituent groups includebranched, straight-chain or cyclic alkyls, mono- or polycyclic aryls,branched, straight-chain or cyclic heteroalkyls, mono- or polycyclicheteroaryls, halos, branched, straight-chain or cyclic haloalkyls,hydroxyls, oxos, thioxos, branched, straight-chain or cyclic alkoxys,branched, straight-chain or cyclic haloalkoxys, trifluoromethoxys, mono-or polycyclic aryloxys, mono- or polycyclic heteroaryloxys, ethers,alcohols, sulfides, thioethers, sulfanyls (thiols), imines, azos,azides, amines (primary, secondary and tertiary), nitriles (any isomer),cyanates (any isomer), thiocyanates (any isomer), nitrosos, nitros,diazos, sulfoxides, sulfonyls, sulfonic acids, sulfamides, sulfonamides,sulfamic esters, aldehydes, ketones, carboxylic acids, esters, amides,amidines, formadines, amino acids, acetylenes, carbamates, lactones,lactams, glucosides, gluconurides, sulfones, ketals, acetals,thioketals, oximes, oxamic acids, oxamic esters, etc., and combinationsof these groups. Substituent groups bearing reactive functionalities maybe protected or unprotected, as is well-known in the art.

“Protecting group” refers to a group of atoms that, when attached to areactive functional group in a molecule, mask, reduce or prevent thereactivity of the functional group. Typically, a protecting group may beselectively removed as desired during the course of a synthesis.Examples of protecting groups can be found in Greene and Wuts,Protective Groups in Organic Chemistry, 3.sup.rd Ed., 1999, John Wiley &Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods,Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative aminoprotecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl(“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl(“TES”), trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxyl protecting groupsinclude, but are not limited to, those where the hydroxyl group iseither acylated or alkylated such as benzyl and trityl ethers, as wellas alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g.,TMS or TIPPS groups) and allyl ethers.

Unless indicated otherwise, the nomenclature of substituents that arenot explicitly defined herein are arrived at by naming the terminalportion of the functionality followed by the adjacent functionalitytoward the point of attachment. For example, the substituent“arylalkyloxycarbonyl” refers to the group (aryl)-(alkyl)-O—C(O)—.

It is understood that in all substituted groups defined above, polymersarrived at by defining substituents with further substituents tothemselves (e.g., substituted aryl having a substituted aryl group as asubstituent which is itself substituted with a substituted aryl group,which is further substituted by a substituted aryl group, etc.) are notintended for inclusion herein. In such cases, the maximum number of suchsubstitutions is three. For example, serial substitutions of substitutedaryl groups are limited to -substituted aryl-(substitutedaryl)-substituted aryl.

Similarly, it is understood that the above definitions are not intendedto include impermissible substitution patterns (e.g., methyl substitutedwith 5 fluoro groups). Such impermissible substitution patterns areeasily recognized by a person having ordinary skill in the art.

C. Methods of Treating Cardiovascular Disorders

This invention provides novel methods of treating cardiovasculardisorders, in particular inflammation-related cardiovascular disorders,including, without limitation, atherosclerosis and cardiomyopathyutilizing Syk kinase inhibitors and 2,4-pyrimidinediamine compounds andprodrugs of the compounds. Given the severity of and suffering caused byatherosclerosis, it is vital that new treatments are developed to treatthese conditions.

In another aspect, disclosed are methods for treating neurologicaldisorders, in particular neurodegenerative and autoimmune-associatedneurological disorders. Examples of neurodegenerative andautoimmune-associated disorders that can be treated according to thepresent methods include, without limitation, stiff person syndrome,Guillain-Barré syndrome, paraneoplastic neurological disorders, movementdisorders (such as arising from Sydenham's chorea), amyotrophic lateralsclerosis, Alzheimer's disease, Parkinson's disease.

Active 2,4-pyrimidinediamine compounds of the invention inhibit Fcreceptor signaling cascades that lead to, among other things,degranulation of mast cells and platelets. As a specific example, thecompounds inhibit the FcεRI and/or FcyR signal cascades that lead todegranulation of immune cells such as mast cells. Both mast cells andplatelets play a central role in the development and progression ofatherosclerosis. Upon activation, the IgE receptor signal transductionpathway is activated, which leads to degranulation of the cells andconsequent release and/or synthesis of a host of chemical mediators,including histamine, proteases (e.g., tryptase and chymase), lipidmediators such as leukotrienes (e.g., LTC4), platelet-activating factor(PAP) and prostaglandins (e.g., PGD2) and a series of cytokines,including TNF-a, IL-4, IL-13, IL-5, IL-6, IL-8, GMCSF, VEGF and TGF-β.The release and/or synthesis of these mediators from mast cells can leadto degradation of the extracellular matrix, deposition of fatty streaksin the vasculature and rupture of existing atherosclerotic plaques.

The molecular events in the Fc receptor signal transduction pathway thatlead to release of preformed mediators via degranulation and releaseand/or synthesis of other chemical mediators are well-known and areillustrated in FIG. 1. Referring to FIG. 1, the Fc receptor is aheterotetrameric receptor composed of an Ig-binding alpha-subunit, abeta subunit, and two gamma subunits (gamma homodimer). Cross-linking ofantibody-bound Fc receptors induces the rapid association and activationof the Src-related kinase Lyn. Lyn phosphorylates immunoreceptortyrosine-based activation motifs (ITAMS) on the intracellular beta andgamma subunits, which leads to the recruitment of additional Lyn to thebeta subunit and Syk kinase to the gamma homodimer. Thesereceptor-associated kinases, which are activated by intra- andintermolecular phosphorylation, phosphorylated other components of thepathway, such as the Btk kinase, LAT, and phospholipase C-gammaPLC-gamma). Activated PLC-gamma initiates pathways that lead to proteinkinase C activation and Ca2+ mobilization, both of which are requiredfor degranulation. FcERI cross-linking also activates the three majorclasses of mitogen activated protein (MAP) kinases, i.e. ERKI/2, JNKI/2,and p38. Activation of these pathways is important in thetranscriptional regulation of proinflammatory mediators, such as TNF-αand IL-6, as well as the lipid mediator leukotriene CA (LTC4). Althoughnot illustrated, the FcyR signaling cascade is believed to share somecommon elements with the FcεRI signaling cascade. Importantly, likeFcεRI, the FcyRI includes a gamma homodimer that is phosphorylated andrecruits Syk, and like FcεRI, activation of the FcyRI signaling cascadeleads to, among other things, degranulation. Other Fc receptors thatshare the gamma homodimer, and which can be regulated by the active2,4-pyrimidinediamine compounds include, but are not limited to, FcaRIand FcyIII.

The ability of the 2,4-pyrimidinediamine compounds of the invention toinhibit Fc receptor signaling cascades may be simply determined orconfirmed in in vitro assays. Suitable assays for confirming inhibitionof FcεRI mediated degranulation are provided in the Examples section. Inone typical assay, cells capable of undergoing FcεRI-mediateddegranulation, such as mast or basophil cells, are first grown in thepresence of IL-4, Stem Cell Factor (SCF), IL-6 and IgE to increaseexpression of the FcεRI, exposed to a 2,4-pyrimidinediamine testcompound of the invention and stimulated with anti-IgE antibodies (or,alternatively, an IgE-specific allergen). Following incubation, theamount of a chemical mediator or other chemical agent released and/orsynthesized as a consequence of activating the FcεRI signaling cascademay be quantified using standard techniques and compared to the amountof the mediator or agent released from control cells (i.e., cells thatare stimulated but that are not exposed to test compound). Theconcentration of test compound that yields a 50% reduction in thequantity of the mediator or agent measured as compared to control cellsis the IC₅₀ of the test compound. The origin of the mast or basophilcells used in the assay will depend, in part, on the desired use for thecompounds and will be apparent to those of skill in the art. Forexample, if the compounds will be used to treat or prevent a particulardisease in humans, a convenient source of mast or basophil cells is ahuman or other animal which constitutes an accepted or known clinicalmodel for the particular disease. Thus, depending upon the particularapplication, the mast or basophil cells may be derived from a widevariety of animal sources, ranging from, for example, lower mammals suchas mice and rats, to dogs, sheep and other mammals commonly employed inclinical testing, to higher mammals such as monkeys, chimpanzees andapes, to humans. Specific examples of cells suitable for carrying outthe in vitro assays include, but are not limited to, rodent or humanbasophil cells, rat basophil leukemia cell lines, primary mouse mastcells (such as bone marrow-derived mouse mast cells “BMMC”) and primaryhuman mast cells isolated from cord blood (“CHMC”) or other tissues suchas lung. Methods for isolating and culturing these cell types arewell-known (see, e.g., Demo et al., 1999, Cytometry 36(4):340-348 andU.S. Pat. No. 7,060,827, the disclosures of which are incorporatedherein by reference). Of course, other types of immune cells thatdegranulate upon activation of the FcεRI signaling cascade may also beused, including, for example, eosinophils.

Accordingly, the activity of the 2,4-pyrimidinediamine compounds of theinvention may also be confirmed in biochemical or cellular assays of Sykkinase activity. In the FcεRI signaling cascade in mast and/or basophilcells, Syk kinase phosphorylates LAT and PLC-gamma1, which leads to,among other things, degranulation. Any of these activities may be usedto confirm the activity of an anti-atherosclerotic compounds of theinvention. In one embodiment, the activity is confirmed by contacting anisolated Syk kinase, or an active fragment thereof with a compound inthe presence of a Syk kinase substrate (e.g., a synthetic peptide or aprotein that is known to be phosphorylated by Syk in a signalingcascade) and assessing whether the Syk kinase phosphorylated thesubstrate. Alternatively, the assay may be carried out with cells thatexpress a Syk kinase. The cells may express the Syk kinase endogenouslyor they may be engineered to express a recombinant Syk kinase. The cellsmay optionally also express the Syk kinase substrate. Cells suitable forperforming such confirmation assays, as well as methods of engineeringsuitable cells will be apparent to those of skill in the art. Specificexamples of biochemical and cellular assays suitable for confirming theactivity of a Syk inhibitor are provided in the Examples section.Generally, compounds that are Syk kinase inhibitors will exhibit an IC₅₀with respect to a Syk kinase activity, such as the ability of Syk kinaseto phosphorylate a synthetic or endogenous substrate, in an in vitro orcellular assay in the range of about 20 μM or less. Skilled artisanswill appreciate that compounds that exhibit lower IC50s, such as in therange of 10 μM, 1 μM, 100 nM, 10 nM, 1 nM, or even lower, areparticularly useful.

Preferred Syk kinase inhibitors for use in the methods of the inventioninclude compounds of structural formula I:

wherein:

-   -   L¹ and L² are each, independently of one another, selected from        the group consisting of a direct bond and a linker;    -   R² is selected from the group consisting of C₁₋₆ alkyl        optionally substituted with one or more of the same or different        R⁸ groups, C₃₋₈ cycloalkyl optionally substituted with one or        more of the same or different R⁸ groups, cyclohexyl optionally        substituted with one or more of the same or different R⁸ groups,        3-8 membered cycloheteroalkyl optionally substituted with one or        more of the same or different R⁸ groups, C₅₋₁₅ aryl optionally        substituted with one or more of the same or different R⁸ groups,        phenyl optionally substituted with one or more of the same or        different R⁸ groups and 5-15 membered heteroaryl optionally        substituted with one or more of the same or different R⁸ groups;    -   R⁴ is selected from the group consisting of hydrogen, C₁₋₆ alkyl        optionally substituted with one or more of the same or different        R⁸ groups, C₃₋₈ cycloalkyl optionally substituted with one or        more of the same or different R⁸ groups, 3-8 membered        cycloheteroalkyl optionally substituted with one or more of the        same or different R⁸ groups, C₅₋₁₅ aryl optionally substituted        with one or more of the same or different R⁸ groups, and 5-15        membered heteroaryl optionally substituted with one or more of        the same or different R⁸ groups;    -   R⁵ is selected from the group consisting of R⁶, C₁₋₆ alkyl        optionally substituted with one or more of the same or different        R⁸ groups;    -   each R⁶ is independently selected from the group consisting of        hydrogen, an electronegative group, —OR^(d), —SR^(d), C₁₋₃        haloalkyloxy, C₁₋₃ perhaloalkyloxy, —NR^(c)R^(c), halogen, C₁₋₃        haloalkyl, C₁₋₃ perhaloalkyl, —CF₃, —CH₂CF₃, —CF₂CF₃, —CN, —NC,        —OCN, —SCN, —NO, —NO₂, —N₃, —S(O)R^(d), —S(O)₂R^(d),        —S(O)₂OR^(d), —S(O)NR^(c)R^(c); —S(O)₂NR^(c)R^(c), —OS(O)R^(d),        —OS(O)₂R^(c), —OS(O)₂OR^(d), —OS(O)NR^(c)R^(c),        —OS(O)₂NR^(c)R^(c), —C(O)R^(d), —C(O)OR^(d), —C(O)NR^(c)R^(c),        —C(NH)NR^(c)R^(c), —OC(O)R^(d), —SC(O)R^(d), —OC(O)OR^(d),        —SC(O)OR^(d), —OC(O)NR^(c)R^(c), —SC(O)NR^(c)R^(c),        —OC(NH)NR^(c)R^(c), —SC(NH)NR^(c)R^(c), —[NHC(O)]_(n)R^(d)—,        —[NHC(O)]_(n)OR^(d), —[NHC(O)]_(n)NR^(c)R^(c) and        —[NHC(NH)]_(n)NR^(c)R^(c), C₅₋₁₀ aryl optionally substituted        with one or more of the same or different R⁸ groups, C₆₋₁₆        arylalkyl optionally substituted with one or more of the same or        different R⁸ groups, 5-10 membered heteroaryl optionally        substituted with one or more of the same or different R⁸ groups        and 6-16 membered heteroarylalkyl optionally substituted with        one or more of the same or different R⁸ groups;    -   R⁸ is selected from the group consisting of R^(e), R^(b), R^(e)        substituted with one or more of the same or different R^(a) or        R^(b), —OR^(a) substituted with one or more of the same or        different R^(a) or R^(b), —B(OR^(a))₂, —B(NR^(c)R^(c))₂,        —(CH₂)_(m)—R^(b), —(CHR^(a))_(m)—R^(b), —O—(CH₂)_(m)—R^(b),        S(CH₂)_(m)—R^(b), —O—CHR^(a)R^(b), —O—CR^(a)(R^(a))₂,        —O—(CHR^(a))_(m)—R^(b), —O—(CH₂)_(m)—CH[(CH₂)_(m)R^(b)]R^(b),        —S—(CHR^(a))_(m)—R^(b); —C(O)NH—(CH₂)_(m)—R^(b),        —C(O)NH—(CHR^(a))_(m)—R^(b), —O(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),        —S—(CH₂)_(m)—R^(b), —C(O)NH—(CH₂)_(m)R^(b),        —O—(CHR^(a))_(m)—C(O)NH—(CHR.s-up.a)_(m)-R^(b),        —S—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b),        —NH—(CH₂)_(m)—R^(b), —NH—(CHR^(a))_(m)—R^(b),        —NH[(CH₂)_(m)R^(b)], —N[(CH₂)_(m)R^(b)]₂,        —NH—C(O)—NH—(CH₂)_(m)—R^(b), —NH—C(O)—(CH₂)_(m)—CHR^(b)R^(b) and        —NH—(CH₂)_(m)—C(O)—NH—(CH₂)_(m)—R^(b);    -   each R^(a) is independently selected from the group consisting        of hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₄₋₁₁ cycloalkylalkyl,        C₅₋₁₀ aryl, C₆₋₁₆ arylalkyl, 2-6 membered heteroalkyl, 3-8        membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl,        5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;    -   each R^(b) is independently selected from the group consisting        of ═O, —OR^(d), (C1-C3) haloalkyloxy, —OCF₃, ═S, —SR^(d),        ═NR^(d), ═NOR^(d), —NR^(c)R^(c), halogen, —CF₃, —CN, —NC, —OCN,        —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(d), —S(O)₂R^(d),        —S(O)₂OR^(d), —S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(d),        —OS(O)₂R^(d), —OS(O)₂OR^(d), —OS(O)₂NR^(c)R^(c), —C(O)R^(d),        —C(O)OR^(d), —C(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c),        —C(NR^(a))NR^(c)R^(c), —C(NOH)R^(a), —C(NOH)NR^(c)R^(c),        —OC(O)R^(d), —OC(O)OR^(d), —OC(O)NR^(c)R^(c),        —OC(NH)NR^(c)R^(c), —OC(NR^(a))NR^(c)R^(c), —[NHC(O)]_(n)R^(d),        —[NR^(a)C(O)]_(n)R^(d), —[NHC(O)]_(n)OR^(d),        —[NR^(a)C(O)]_(n)OR^(d), —[NHC(O)]_(n)NR^(c)R^(c),        —[NR^(a)C(O)]_(n)NR^(c)R^(c), —[NHC(NH)]_(n)NR^(c)R^(c) and        —[NR^(a)C(NR^(a))]_(n)NR^(c)R^(c);    -   each R^(c) is independently a protecting group or R^(a), or,        alternatively, each R^(c) is taken together with the nitrogen        atom to which it is bonded to form a 5 to 8-membered        cycloheteroalkyl or heteroaryl which may optionally include one        or more of the same or different additional heteroatoms and        which may optionally be substituted with one or more of the same        or different R^(a) or R^(b) groups;    -   each R^(d) is independently a protecting group or R^(a);    -   each R^(e) is independently selected from the group consisting        of C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₄₋₁₁ cycloalkylalkyl, C₅₋₁₀        aryl, C₆₋₁₆ arylalkyl, 2-6 membered heteroalkyl, 3-8 membered        cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10        membered heteroaryl and 6-16 membered heteroarylalkyl;    -   each m is independently an integer from 1 to 3; and    -   each n is independently an integer from 0 to 3.

In a preferred implementation, R⁶ is hydrogen and each of L¹ and L² is adirect bond. More preferably, R⁵ is selected from the group consistingof halo, —CN, —NO₂, —C(O)R^(a), —C(O)OR^(a), —C(O)CF₃, —C(O)OCF₃, C₁₋₃haloalkyl, C₁₋₃ perhaloalkyl, C₁₋₃ haloalkoxy, C₁₋₃ perhaloalkoxy, —OCF₃and —CF₃. In a particularly preferred implementation, R⁵ is fluoro. Inyet another implementation, R² is selected from the group consisting ofphenyl, naphthyl, and 5-10 membered heteroaryl, optionally substitutedwith one or more of the same or different R⁸ groups. Preferably R² isselected from the group consisting of benzodioxanyl, 1,4-benzodioxan-(5or 6)-yl, benzodioxolyl, 1,3-benzodioxol-(4 or 5)-yl, benzoxazinyl,1,4-benzoxazin-(5, 6, 7 or 8)-yl, benzoxazolyl, 1,3-benzoxazol-(4, 5, 6or 7)-yl, benzopyranyl, benzopyran-(5, 6, 7 or 8)-yl, benzotriazolyl,benzotrazol-(4, 5, 6 or 7)-yl, 1,4-benzoxazinyl-2-one,1,4-benzoxazin-(5, 6, 7 or 8)-yl-2-one, 2H-1,4-benzoxazinyl-3(4H)-one,2H-1,4-benzoxazin-(5, 6, 7 or 8)-yl-3(4H)-one,2H-1,3-benzoxazinyl-2,4(3H)-dione, 2H-1,3-benzoxazin-(5, 6, 7 or8)-yl-2,4(3H)-dione, benzoxazolyl-2-one, benzoxazol-(4, 5, 6 or7)-yl-2-one, dihydrocoumarinyl, dihydrocoumarin-(5, 6, 7 or 8)-yl,1,2-benzopyronyl, 1,2-benzopyron-(5, 6, 7 or 8)-yl, benzofuranyl,benzofuran-(4, 5, 6 or 7)-yl, benzo[b]furanyl, benzo[b]furan-(4, 5, 6,or -7)-yl, indolyl, indol-(4, 5, 6 or 7)-yl, pyrrolyl and pyrrol-(1 or2)-yl, optionally substituted with one or more of the same of differentR⁸ groups.

In one implementation of the invention, one or both of R² and R⁴ are,independently of one another, is a heteroaryl selected from the groupconsisting of:

wherein:

-   -   p is an integer from one to three;    -   each - - - independently represents a single bond or a double        bond;    -   R³⁵ is hydrogen or R⁸;    -   X is selected from the group consisting of CH, N and N—O;    -   each Y is independently selected from the group consisting of O,        S and NH;    -   each Y¹ is independently selected from the group consisting of        O, S, SO, SO₂, SONR³⁶, NH and NR³⁷;    -   each Y² is independently selected from the group consisting of        CH, CH₂, O, S, N, NH and NR³⁷;    -   R³⁶ is hydrogen or alkyl;    -   R³⁷ is selected from the group consisting of hydrogen and a        progroup,    -   R³⁸ is selected from the group consisting of alkyl and aryl;    -   A is selected from the group consisting of O, NH and NR³⁸;    -   R⁹, R¹⁰, R¹¹ and R¹² are each, independently of one another,        selected from the group consisting of alkyl, alkoxy, halogen,        haloalkoxy, aminoalkyl and hydroxyalkyl, or, alternatively, R⁹        and R¹⁰ or R¹¹ and R¹², or R⁹ and R¹⁰ and R¹¹ and R¹² are taken        together form an oxo group;    -   each Z is selected from the group consisting of hydroxyl,        alkoxy, aryloxy, ester, and carbamate;    -   Q is selected from the group consisting of —OH, OR⁸,        —NR^(c)R^(c), —NHR³⁹—C(O)R⁸, —NHR³⁹—C(O)OR⁸, —NR³⁹—CHR⁴⁰—R^(b),        —NR³⁹—(CH₂)_(m)—R^(b) and —NR³⁹—C(O)—CHR⁴⁰—NR^(c)R^(c); and    -   R³⁹ and R⁴⁰ are each, independently of one another, selected        from the group consisting of hydrogen, alkyl, aryl, alkylaryl,        arylalkyl and NHR⁸.

In a preferred implementation, R² is phenyl substituted with one or moreR⁸ groups. More preferably, R² is phenyl substituted with one to threealkoxy groups.

In another preferred implementation, R⁴ is

One aspect of the invention provides methods of treating atherosclerosisor regressing or decreasing formation of arterial atheroscleroticlesions, said method comprising administering to a mammal havingatherosclerosis an effective amount of a compound of formula III:

wherein each of R² and R⁴ independently is phenyl substituted with oneor more R⁸ groups or a heteroaryl selected from the group consisting of

wherein:

-   -   R³⁵ is hydrogen or R⁸;    -   R⁸ is R^(a), R^(b), R^(e) substituted with one or more of the        same or different R^(a) or R^(b), —OR^(a) substituted with one        or more of the same or different R^(a) or R^(b), —B(OR^(a))₂,        —B(NR^(c)R^(c))₂, —(CH₂)_(m)—R^(b), —(CHR^(a))_(m)—R^(b),        —O—(CH₂)_(m)—R^(b), —S—(CH₂)_(m)—R^(b), —O—CHR^(a)R^(b),        —O—CR^(a)(R^(b))₂, —O—(CHR^(a))_(m)—R^(b),        —O—(CH₂)_(m)—CH[(CH₂)_(m)R^(b)]R^(b), —S—(CHR^(a))_(m)—R^(b),        —C(O)NH—(CH₂)_(m)—R^(b), —C(O)NH—(CHR^(a))_(m)—R^(b),        —O—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),        —S—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),        —O—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b),        —S—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b),        —NH—(CH₂)_(m)—R^(b), —NH—(CHR^(a))_(m)—R^(b),        —NH[(CH₂)_(m)R^(b)], —N[(CH₂)_(m)R^(b)]₂,        —NH—C(O)—NH—(CH₂)_(m)—R^(b), —NH—C(O)—(CH₂)_(m)—CHR^(b)R^(b) or        —NH—(CH₂)_(m)—C(O)—NH—(CH₂)_(m)—R^(b);    -   each R^(a) is independently selected from the group consisting        of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl,        (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16)        arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered        cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl,        piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered        heteroaryl and 6-16 membered heteroarylalkyl;    -   each R^(b) is independently selected from the group consisting        of ═O, —OR^(d), (C1-C3) haloalkyloxy, —OCF₃, ═S, —SR^(d),        ═NR^(d), ═NOR^(d), —NR^(c)R^(c), halogen, —CF₃, —CN, —NC, —OCN,        —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(d), —S(O)₂R^(d),        —S(O)₂OR^(d), —S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(d),        —OS(O)₂R^(d), —OS(O)₂OR^(d), —OS(O)₂NR^(c)R^(c), —C(O)R^(d),        —C(O)OR^(d), —C(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c),        —C(NR^(a))NR^(c)R^(c), —C(NOH)R^(a), —C(NOH)NR^(c)R^(c),        —OC(O)R^(d), —OC(O)OR^(d), —OC(O)NR^(c)R^(c),        —OC(NH)NR^(c)R^(c), —OC(NR^(a))NR^(c)R^(c), —[NHC(O)]_(n)R^(d),        —[NR^(a)C(O)]_(n)R^(d), —[NHC(O)]_(n)OR^(d),        —[NR^(a)C(O)]_(n)OR^(d), —[NHC(O)]_(n)NR^(c)R^(c),        —[NR^(a)C(O)]_(n)NR^(c)R^(c), —[NHC(NH)]_(n)NR^(c)R^(c) and        —[NR^(a)C(NR^(a))]_(n)NR^(c)R^(c);    -   each R^(c) is independently a protecting group or R^(a), or,        alternatively, two R^(c) are taken together with the nitrogen        atom to which they are bonded to form a 5 to 8-membered        cycloheteroalkyl or heteroaryl which may optionally include one        or more of the same or different additional heteroatoms and        which may optionally be substituted with one or more of the same        or different R^(a) or R^(b) groups;    -   each R^(d) is independently a protecting group or R^(a);    -   each R^(e) is independently selected from the group consisting        of (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11)        cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl,        benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl,        morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11        membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and        6-16 membered heteroarylalkyl;    -   X is selected from the group consisting of CH, N and N—O;    -   each Y independently is selected from the group consisting of O,        S and NH;    -   each Y¹ independently is selected from the group consisting of        O, S, SO, SO₂, SONR³⁶, NH and NR³⁵;    -   each Y² independently is selected from the group consisting of        CH, CH₂, O, S, N, NH and NR³⁵;    -   each R³⁶ independently is hydrogen or alkyl;    -   A is selected from the group consisting of O, NH and NR³⁸;    -   Q is selected from the group consisting of —OH, OR⁸,        —NR^(c)R^(c), NHR³⁹C(O)R⁸, —NHR³⁹—C(O)OR⁸, —NR³⁹—CHR⁴⁰—R^(b),        —NR³⁹—(CH₂)_(m)—R^(b) and —NR³⁹—C(O)—CHR⁴⁰—NR^(c)R^(c);    -   each R³⁸ independently is selected from the group consisting of        alkyl and aryl;    -   R⁹, R¹⁰, R¹¹ and R¹² are each, independently of one another,        selected from the group consisting of alkyl, alkoxy, halogen,        haloalkoxy, aminoalkyl and hydroxyalkyl, or, alternatively, R⁹        and R¹⁰ or R¹¹ and R¹², or R⁹ and R¹⁰ and R¹¹ and R¹² are taken        together form an oxo group;    -   each Z is selected from the group consisting of hydroxyl,        alkoxy, aryloxy, ester, and carbamate;    -   Q is selected from the group consisting of —OH, OR⁸,        —NR^(c)R^(c), —NHR³⁹—C(O)R⁸, —NHR³⁸—C(O)OR⁸, —NR³⁸—CHR⁴⁰—R^(b),        —NR³⁸—(CH₂)_(m)—R^(b) and —NR³⁸—C(O)—CHR⁴⁰—NR^(c)R^(c); and    -   R³⁹ and R⁴⁰ are each, independently of one another, selected        from the group consisting of hydrogen, alkyl, aryl, alkylaryl,        arylalkyl and NHR⁸; and    -   each m independently is an integer from 1 to 3; and    -   each n is independently an integer from 0 to 3.

In certain implementations, the compound administered to the mammal inneed thereof is a prodrug of a Syk kinase inhibitor. The prodrugsgenerally comprise a biologically active 2,4-pyrimidinediamine compoundthat is substituted at the nitrogen atom of one or more primary orsecondary amine groups with a progroup (R^(P)) that metabolizes orotherwise transforms under conditions of use to yield the active2,4-pyrimidinediamine. In some embodiments, the progroup is aphosphorous-containing progroup. In some embodiments, the progroupincludes a group or moiety that is metabolized under the conditions ofuse to yield an unstable α-hydroxymethyl α-aminomethyl or α-thiomethylintermediate, which then further metabolized in vivo to yield the active2,4-pyrimidinediamine drug. In some embodiments, the progroup includesan α-hydroxyalkyl, α-aminoalkyl or α-thioalkyl moiety, for example anα-hydroxymethyl, α-aminomethyl, α-thiomethyl moiety, that metabolizesunder the conditions of use to yield the active 2,4 pyrimidinediaminedrug. For example, in some embodiments the progroup is of the formula—(CR^(d)R^(d))_(y)-A-R³, where y is 1, 2 or 3, each R^(d) is,independently of the other, selected from hydrogen, cyano, optionallysubstituted (C1-C20) alkyl, (C1-C20) perfluoroalkyl, optionallysubstituted (C7-C30) arylalkyl and optionally substituted 6-30 memberedheteroarylalkyl, where each optional substituent is, independently ofthe others, selected from hydrogen, alkyl, aryl, arylalkyl, heteroaryland heteroalkyl, or, alternatively, the two R^(d) are taken togetherwith the carbon atom to which they are bonded to form a cycloalkylcontaining from 3 to 8 carbon atoms; A is selected from O, S and NR⁵⁰,where R⁵⁰ is selected from hydrogen, alkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl and cycloheteroalkyl, or alternatively is combined withR³, and, together with the nitrogen to which they are attached, form a3-7 membered ring; and R³ represents a group that can be metabolized invivo to yield a group of the formula —CR^(d)R^(d)-AH, where R^(d) and Aare as previously defined.

The identity of R³ is not critical, provided that it can be metabolizedunder the desired conditions of use, for example under the acidicconditions found in the stomach and/or by enzymes found in vivo, toyield a group of the formula —CR^(d)R^(d)-AH, where A and R^(d) are aspreviously defined. Thus, skilled artisans will appreciate that R³ cancomprise virtually any known or later-discovered hydroxyl, amine orthiol protecting group. Non-limiting examples of suitable protectinggroups can be found, for example, in Protective Groups in OrganicSynthesis, Greene & Wuts, 2nd Ed., John Wiley & Sons, New York, 1991(especially pages 10-142 (alcohols, 277-308 (thiols) and 309-405(amines) the disclosure of which is incorporated herein by reference).

In a specific embodiment, R³ includes, together with A, an ether, athioether, a silyl ether, a silyl thioether, an ester, a thioester, anamide, a carbonate, a thiocarbonate, a carbamate, a thiocarbamate, or aurea linkage, —OCH₂SO₃R, where R is hydrogen, alkyl, aryl, arylalkyl ora metal salt (e.g., sodium, lithium, potassium); -GCH₂N⁺(R⁵¹)₃M⁻, whereG is absent, —OPO₃ ⁻, OSO₃ ⁻ or —CO₂ ⁻, R⁵¹ is hydrogen, alkyl, aryl,arylalkyl, cycloheteroalkyl or cycloheteroalkylalkyl and M- is acounterion, usually a halide ion or the like (acetate, sulfate,phosphate, etc.). Specific exemplary embodiments include, but are notlimited to, progroups R^(P) in which R³ is selected from R^(f),—C(O)R^(f), —C(O)OR^(f), —C(O)NR^(f)R^(f) and —SiR^(f)R^(f)R^(f), whereeach R^(f) is, independently of the others, selected from hydrogen,optionally substituted lower alkyl, optionally substituted lowerheteroalkyl, optionally substituted lower cycloalkyl, optionallysubstituted lower heterocycloalkyl, optionally substituted (C6-C10)aryl, optionally substituted 5-10 membered heteroaryl, optionallysubstituted (C7-C18) arylalkyl and optionally substituted 6-18 memberedheteroarylalkyl. In a specific embodiment, each R^(f) is the same.

The identity of the progroup(s) can be selected to tailor thewater-solubility and other properties of the underlying active2,4-pyrimidinediamine compound to be optimized for a particular mode ofadministration. It can also be selected to provide for removal atspecified organs and/or tissues within the body, such as, for example,in the digestive tract, in blood and/or serum, or via enzymes residingin specific organs, such as the liver.

In some embodiments, progroups that are phosphorous-containing progroupsinclude phosphate moieties that can be cleaved in vitro by enzymes suchas esterases, lipases and/or phosphatases. Such enzymes are prevalentthroughout the body, residing in, for example, the stomach and digestivetract, blood and/or serum, and in virtually all tissues and organs. Suchphosphate-containing progroups will generally increase thewater-solubility of the underlying active 2,4-pyrimidinediaminecompound, making such phosphate-containing prodrugs ideally suited formodes of administration where water-solubility is desirable, such as,for example, oral, buccal, intravenous, intramuscular and ocular modesof administration.

In some embodiments, each phosphate-containing progroup in the prodrugis of the formula —(CR^(d)R^(d))_(y)—O—P(O)(OH)(OH), or a salt thereof,wherein y and R^(d) are as previously defined. In one specificembodiment, each R^(d) is, independently of the others, selected fromthe group consisting of hydrogen, substituted or unsubstituted loweralkyl, substituted or unsubstituted phenyl, substituted or unsubstitutedmethyl and substituted or unsubstituted benzyl. In another specificembodiment, each R^(d) is, independently of the others, selected fromthe group consisting of hydrogen and unsubstituted lower alkyl. Specificexemplary phosphate-containing progroups RP include —CH₂—O—P(O)(OH)(OH)and —CH₂CH₂—O—P(O)(OH)(OH) and/or the corresponding salts.

A preferred prodrug for use in the methods of the invention includescompounds of structural formula II:

wherein:

-   -   Y is selected from CH₂, NR²⁴, O, S, S(O) and S(O)₂;    -   Z¹ and Z² each, independently of one another, are selected from        CH and N;    -   R² is selected from the group consisting of (CI-C6) alkyl        optionally substituted with one or more of the same or different        R⁸ groups, (C3-C8) cycloalkyl optionally substituted with one or        more of the same or different R⁸ groups, 3-8 membered        cycloheteroalkyl optionally substituted with one or more of the        same or different R⁸ groups, (C6-C14) aryl optionally        substituted with one or more of the same or different R⁸ groups,        and 5-15 membered heteroaryl optionally substituted with one or        more of the same or different R⁸ groups;    -   R⁵ is selected from halo, cyano, nitro, and trihalomethyl;    -   R⁸ is selected from the group consisting of R^(a), R^(b), R^(a)        substituted with one or more of the same or different R^(a) or        R^(b), —OR^(a) substituted with one or more of the same or        different R^(a) or R^(b), —B(OR^(a))₂, —B(NR^(c)R^(c))₂,        —(CH₂)_(m)—R^(b), —(CHR^(a))_(m)—R^(b), —O—(CH₂)_(m)—R^(b),        —S—(CH₂)_(m)—R^(b), —O—CHR^(a)R^(b), —O—CR^(a)(R^(b))₂,        —O—(CHR^(a))_(m)—R^(b), —O—(CH₂)_(m)—CH[(CH₂)_(m)R^(b)]R^(b),        —S—(CHR^(a))_(m)—R^(b), —C(O)NH—(CH₂)_(m)—R^(b),        —C(O)NH—(CHR^(a))_(m)—R^(b), —O—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b)        —S—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),        —O—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b),        —S—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b),        —NH—(CH₂)_(m)—R^(b), —NH—(CHR^(a))_(m)—R^(b),        —NH[(CH₂)_(m)R^(b)], —N[(CH₂)_(m)R^(b)]₂,        —NH—C(O)—NH—(CH₂)_(m)—R^(b) , —NH—C(O)—(CH₂)_(m)—CHR^(b)R^(b)        and —NH—(CH₂)_(m)—C(O)—NH—(CH₂)_(m)—R^(b);    -   R¹⁷ is selected from the group consisting of hydrogen, halogen,        and lower alkyl or, alternatively, R¹⁷ may be taken together        with R¹⁸ to form an oxo (═O) group or, together with the carbon        atom to which they are attached, a spirocycle containing from 3        to 7 carbon atoms;    -   R¹⁸ is selected from the group consisting of hydrogen, halogen,        and lower alkyl or, alternatively, R¹⁸ may be taken together        with R¹⁷ to form an oxo (═O) group or, together with the carbon        atom to which they are attached, a spirocycle containing from 3        to 7 carbon atoms;    -   R¹⁹ is selected from the group consisting of hydrogen and lower        alkyl or, alternatively, R¹⁹ may be taken together with R²⁰ to        form an oxo (═O) group or, together with the carbon atom to        which they are attached, a spirocycle containing from 3 to 7        carbon atoms;    -   R²⁰ is selected from the group consisting of hydrogen and lower        alkyl or, alternatively, R²⁰ may be taken together with R¹⁹ to        form an oxo (═O) group or, together with the carbon atom to        which they are attached, a spirocycle containing from 3 to 7        carbon atoms;    -   each R^(a) is, independently of the others, selected from the        group consisting of hydrogen, lower alkyl, lower cycloalkyl,        (C4-C11) cycloalkylalkyl, (C6-C10) aryl, (C7-C16) arylalkyl, 2-6        membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11        membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and        6-16 membered heteroarylalkyl;    -   each R^(b) is independently selected from the group consisting        of ═O, —OR^(a), (C1-C3) haloalkyloxy, ═S, —SR^(a), ═NR^(a),        ═NOR^(a), —NR^(c)R^(c), halogen, —CF₃, —CN, —NC, —OCN, —SCN,        —NO, —NO₂, ═N₂, —N₃, —S(O)R^(a), —S(O)₂R^(a), —S(O)₂OR^(a),        —S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),        —OS(O)₂OR^(a), —OS(O)₂NR^(c)R^(c), —C(O)R^(a), —C(O)OR^(a),        —C(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c), —C(NR^(a))NR^(c)Rc,        —C(NOH)R^(a), —C(NOH)NR^(c)R^(c), —OC(O)R^(a), —OC(O)OR^(a),        —OC(O)NR^(c)R^(c), —OC(NH)NR^(c)R^(c), —OC(NR^(a))NR^(c)R^(c),        —[NHC(O)]_(n)R^(a), —[NR^(a)C(O)]_(n)R^(a), —[NHC(O)]_(n)OR^(a),        —[NR^(a)C(O)]_(n)OR^(a), —[NHC(O)]_(n)NR^(c)R^(c),        —[NR^(a)C(O)]_(n)NR^(c)R^(c), —[NHC(NH)]_(n)NR^(c)R^(c) and        —[NR^(a)C(NR^(a))]_(n)NR^(c)R^(c);    -   each R^(c) is, independently of the others, selected from the        group consisting of a protecting group and R^(a), or,        alternatively, the two R^(c) bonded to the same nitrogen atom        are taken together with that nitrogen atom to form a 5 to        8-membered cycloheteroalkyl or heteroaryl which may optionally        include one or more of the same or different additional        heteroatoms and which may optionally be substituted with one or        more of the same or different R^(a) groups;    -   R²¹, R²² and R²³ are each, independently of one another,        selected from the group consisting of hydrogen and a progroup        R^(P);    -   R^(P) has the formula —(CR^(d)R^(d))_(y)-A-R³, where y is an        integer ranging from 1 to 3; A is O or S; each R^(d) is,        independently of the others, selected from the group consisting        of hydrogen, optionally substituted lower alkyl, optionally        substituted (C6-C14) aryl and optionally substituted (C7-C20)        arylalkyl; where the optional substituents are, independently of        one another, selected from hydroxyl, lower alkoxy, (C6-C14)        aryloxy, lower alkoxyalkyl and halogen, or, alternatively, two        R^(d) bonded to the same carbon atom, taken together with the        carbon atom to which they are bonded, form a cycloalkyl group        containing from 3 to 8 carbon atoms;    -   R³ comprises, together with the heteroatom, A, to which it is        bonded, an alcohol, an ether, a thioether, a silyl ether, a        silyl thioether, an ester, a thioester, an amide, a carbonate, a        thiocarbonate, a carbamate, a thiocarbamate, a urea, a        phosphate, a phosphate salt or a phosphate ester;    -   each m is, independently of the others, an integer from 1 to 3;        and    -   each n is, independently of the others, an integer from 0 to 3,        with the proviso that at least one of R²¹, R²², and R²³ is        R^(P).

In therapeutic use, the compounds of the present invention are usuallyadministered in a standard pharmaceutical composition. The presentinvention therefore provides, in a further aspect, a pharmaceuticalcomposition comprising a compound of formula (I) and a pharmaceuticallyacceptable carrier.

In a particular embodiment, there is one progroup R^(P), and in moreparticular embodiments, R²¹ is R^(P). In one exemplary embodiment theprodrug is a prodrug of Compound 1. In a specific example, the compoundis N4-(2,2-dimethyl-4-[(dihydrogenphosphonoxy)methyl]-3-oxo-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamineand salts thereof, Compound 4.

When used to treat or prevent such diseases, the active compounds may beadministered singly, as mixtures of one or more active compounds or inmixture or combination with other agents useful for treating suchdiseases and/or the symptoms associated with such diseases. The activecompounds may also be administered in mixture or in combination withagents useful to treat other disorders or maladies, such asanti-hypertensives (such as beta blockers, angiotensin-converting enzyme(ACE) inhibitors and calcium channel blockers), cholesterol medications(such as statin, fibrates, or intestinal cholesterolabsorption-inhibiting supplements, including ezetimibe), anticoagulants(e.g., heparin or warfarin), anti-platelet medications (e.g., low-doseaspirin), niacin, omega-3 fatty acids, and folic acids. The activecompounds may be administered per se in the form of prodrugs or aspharmaceutical compositions, comprising an active compound or prodrug.

Pharmaceutical compositions comprising the active compounds of theinvention (or prodrugs thereof) may be manufactured by means ofconventional mixing, dissolving, granulating, dragee-making levigating,emulsifying, encapsulating, entrapping or lyophilization processes. Thecompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients or auxiliarieswhich facilitate processing of the active compounds into preparationswhich can be used pharmaceutically.

The active compound or prodrug may be formulated in the pharmaceuticalcompositions per se, or in the form of a hydrate, solvate, N-oxide orpharmaceutically acceptable salt, as previously described. Typically,such salts are more soluble in aqueous solutions than the correspondingfree acids and bases, but salts having lower solubility than thecorresponding free acids and bases may also be formed.

Pharmaceutical compositions of the invention may take a form suitablefor virtually any mode of administration, including, for example,topical, ocular, oral, buccal, systemic, nasal, injection, transdermal,rectal, vaginal, etc., or a form suitable for administration byinhalation or insufflation.

For topical administration, the active compound(s) or prodrug(s) may beformulated as solutions, gels, ointments, creams, suspensions, etc. asare well-known in the art.

Systemic formulations include those designed for administration byinjection, e.g., subcutaneous, intravenous, intramuscular, intrathecalor intraperitoneal injection, as well as those designed for transdermal,transmucosal oral or pulmonary administration.

Useful injectable preparations include sterile suspensions, solutions oremulsions of the active compound(s) in aqueous or oily vehicles. Thecompositions may also contain formulating agents, such as suspending,stabilizing and/or dispersing agent. The formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multidosecontainers, and may contain added preservatives.

Alternatively, the injectable formulation may be provided in powder formfor reconstitution with a suitable vehicle, including but not limited tosterile pyrogen free water, buffer, dextrose solution, etc., before use.To this end, the active compound(s) maybe dried by any art-knowntechnique, such as lyophilization, and reconstituted prior to use.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants are knownin the art.

For oral administration, the pharmaceutical compositions may take theform of, for example, lozenges, tablets or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g., lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g., magnesium stearate, talc or silica); disintegrants (e.g., potatostarch or sodium starch glycolate); or wetting agents (e.g., sodiumlauryl sulfate). The tablets may be coated by methods well known in theart with, for example, sugars, films or enteric coatings. Compoundswhich are particularly suitable for oral administration include6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-oneand prodrugs thereof, for example but not limited to,(6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyldihydrogen phosphate and pharmaceutically acceptable salts thereof.

Liquid preparations for oral administration may take the form of, forexample, elixirs, solutions, syrups or suspensions, or they may bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations may be prepared byconventional means with pharmaceutically acceptable additives such assuspending agents (e.g., sorbitol syrup, cellulose derivatives orhydrogenated edible fats); emulsifying agents (e.g., lecithin oracacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethylalcohol, CREMOPHORE™ or fractionated vegetable oils); and preservatives(e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Thepreparations may also contain buffer salts, preservatives, flavoring,coloring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound or prodrug, as is well known.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For rectal and vaginal routes of administration, the active compound(s)may be formulated as solutions (for retention enemas) suppositories orointments containing conventional suppository bases such as cocoa butteror other glycerides.

For nasal administration or administration by inhalation orinsufflation, the active compound(s) or prodrug(s) can be convenientlydelivered in the form of an aerosol spray from pressurized packs or anebulizer with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or othersuitable gas. In the case of a pressurized aerosol, the dosage unit maybe determined by providing a valve to deliver a metered amount. Capsulesand cartridges for use in an inhaler or insufflator (for examplecapsules and cartridges comprised of gelatin) may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

A specific example of an aqueous suspension formulation suitable fornasal administration using commercially-available nasal spray devicesincludes the following ingredients: active compound or prodrug (0.5-20mg/ml); benzalkonium chloride (0.1-0.2 mg/mL); polysorbate 80 (TWEEN®80; 0.5-5 mg/ml); carboxymethylcellulose sodium or microcrystallinecellulose (1-15 mg/ml); phenylethanol (1-4 mg/ml); and dextrose (20-50mg/ml). The pH of the final suspension can be adjusted to range fromabout pH 5 to pH 7, with a pH of about pH 5.5 being typical.

Another specific example of an aqueous suspension suitable foradministration of the compounds via inhalation, and in particular forsuch administration of a 2,4-pyrimidinediamine, contains 1-20 mg/mLCompound or prodrug, 0.1-1% (v/v) Polysorbate 80 (TWEEN® 80), 50 mMcitrate and/or 0.9% sodium chloride.

For prolonged delivery, the active compound(s) or prodrug(s) can beformulated as a depot preparation for administration by implantation orintramuscular injection. The active ingredient maybe formulated withsuitable polymeric or hydrophobic materials (e.g., as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly solublederivatives, e.g., as a sparingly soluble salt. Alternatively,transdermal delivery systems manufactured as an adhesive disc or patchwhich slowly releases the active compound(s) for percutaneous absorptionmay be used. To this end, permeation enhancers may be used tofacilitate-transdermal penetration of the active compound(s). Suitabletransdermal patches are: described in for example, U.S. Pat. No.5,407,713; U.S. Pat. No. 5,352,456; U.S. Pat. No. 5,332,213; U.S. Pat.No. 5,336,168; U.S. Pat. No. 5,290,561; U.S. Pat. No. 5,254,346; U.S.Pat. No. 5,164,189; U.S. Pat. No. 5,163,899; U.S. Pat. No. 5,088,977;U.S. Pat. No. 5,087,240; U.S. Pat. No. 5,008,110; and U.S. Pat. No.4,921,475.

Alternatively, other pharmaceutical delivery systems may be employed.Liposomes and emulsions are well-known examples of delivery vehiclesthat may be used to deliver active compound(s) or prodrug(s). Certainorganic solvents such as dimethylsulfoxide (DMSO) may also be employed,although usually at the cost of greater toxicity.

The pharmaceutical compositions may, if desired, be presented in a packor dispenser device which may contain one or more unit dosage formscontaining the active compound(s). The pack may, for example, comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice may be accompanied by instructions for administration.

The active compound(s) or prodrug(s) of the invention, or compositionsthereof, will generally be used in an amount effective to achieve theintended result, for example in an amount effective to treat or preventthe particular disease being treated. The compound(s) may beadministered therapeutically to achieve therapeutic benefit orprophylactically to achieve prophylactic benefit. By therapeutic benefitis meant eradication or amelioration of the underlying disorder beingtreated and/or eradication or amelioration of one or more of thesymptoms associated with the underlying disorder such that the patientreports an improvement in feeling or condition, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forexample, administration of a compound to a patient suffering fromatherosclerosis provides therapeutic benefit not only when theunderlying deposition of lipids and resulting arterial blockage iseradicated or ameliorated, but also when the patient reports a decreasein the severity or duration of the cardiovascular symptoms. As anotherexample, therapeutic benefit in the context of atherosclerosis includesdecreased rates of lipid deposition, decreased atherogenesis, or areduction in the frequency or severity of cardiac episodes. Therapeuticbenefit also includes halting or slowing the progression of the disease,regardless of whether improvement is realized.

For prophylactic administration, the compound may be administered to apatient at risk of developing atherosclerosis. Alternatively,prophylactic administration may be applied to avoid the onset ofsymptoms in a patient diagnosed with the underlying disorder. Compoundsmay also be administered prophylactically to apparently healthyindividuals who are genetically prone to developing atherosclerosis.

The amount of compound administered will depend upon a variety offactors, including, for example, the particular indication beingtreated, the mode of administration, whether the desired benefit isprophylactic or therapeutic, the severity of the indication beingtreated and the age and weight of the patient, the bioavailability ofthe particular active compound, etc. Determination of an effectivedosage is well within the capabilities of those skilled in the art.

Effective dosages may be estimated initially from in vitro assays. Forexample, an initial dosage for use in animals may be formulated toachieve a circulating blood or serum concentration of active compoundthat is at or above an IC₅₀ of the particular compound as measured in asin vitro assay, such as the in vitro CHMC, platelet or other in vitroassays described in the Examples section. Calculating dosages to achievesuch circulating blood or serum concentrations taking into account thebioavailability of the particular compound is well within thecapabilities of skilled artisans. For guidance, the reader is referredto Fingl & Woodbury, “General Principles,” In: Goodman and Gilman's ThePharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latestedition, Pagamonon Press, and the references cited therein.

Initial dosages can also be estimated from in vivo data, such as animalmodels. Animal models useful for testing the efficacy of compounds totreat or prevent the various diseases described above are well-known inthe art. Suitable animal models of atherosclerosis are described inZadelaar, et al., “Mouse models for atherosclerosis and pharmaceuticalmodifiers,” Arterioscler. thromb. Vasc. Biol. 27(8):1706-21 (2007).Ordinarily skilled artisans can routinely adapt such information todetermine dosages suitable for human administration. Additional suitableanimal models are described in the Examples section.

Dosage amounts will typically be in the range of from about 0.0001 or0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but may be higher orlower, depending upon, among other factors, the activity of thecompound, its bioavailability, the mode of administration and variousfactors discussed above. Dosage amount and interval may be adjustedindividually to provide plasma levels of the compound(s) which aresufficient to maintain therapeutic or prophylactic effect. For example,the compounds may be administered once per week, several times per week(e.g., every other day), once per day or multiple times per day,depending upon, among other things, the mode of administration, thespecific indication being treated and the judgment of the prescribingphysician. In cases of local administration or selective uptake, such aslocal topical administration, the effective local concentration ofactive compound(s) may not be related to plasma concentration. Skilledartisans will be able to optimize effective local dosages without undueexperimentation.

Preferably, the compound(s) will provide therapeutic or prophylacticbenefit without causing substantial toxicity. Toxicity of thecompound(s) may be determined using standard pharmaceutical procedures.The dose ratio between toxic and therapeutic (or prophylactic) effect isthe therapeutic index. Compounds(s) that exhibit high therapeuticindices are preferred.

Compounds of the present invention may also be of use in treating theabove mentioned disease states in combination with ananti-hyperlipidaemic, anti-atherosclerotic, anti-diabetic, anti-anginal,anti-inflammatory, or anti-hypertension agent or an agent for loweringLp(a). Examples of the above include cholesterol synthesis inhibitorssuch as statins, anti-oxidants such as probucol, insulin sensitisers,calcium channel antagonists, and anti-inflammatory drugs such as NSAIDs.Examples of agents for lowering Lp(a) include the aminophosphonatesdescribed in WO 97/02037, WO 98/28310, WO 98/28311 and WO 98/28312(Symphar SA and SmithKline Beecham).

A preferred combination therapy will be the use of a compound of thepresent invention and a statin. The statins are a well known class ofcholesterol lowering agents and include atorvastatin, simvarstatin,pravastatin, cerivastatin, fluvastatin, lovastatin and rosuvastatin(also referred to as S-4522 or ZD 4522, Astra Zeneca). The two agentsmay be administered at substantially the same time or at differenttimes, according to the discretion of the physician.

A further preferred combination therapy will be the use of a compound ofthe present invention and an anti-diabetic agent or an insulinsensitiser, as coronary heart disease is a major cause of death fordiabetics. Within this class, preferred compounds for use with acompound of the present invention include the PPARgamma activators, forinstance G1262570 (GlaxoSmithKline) and the glitazone class of compoundssuch as rosiglitazone (Avandia, GlaxoSmithKline), troglitazone andpioglitazone.

The 2,4-pyrimidinediamine compounds and prodrugs of the invention can besynthesized via a variety of different synthetic routes usingcommercially available starting materials and/or starting materialsprepared by conventional synthetic methods. Suitable exemplary methodsthat can be routinely adapted to synthesize the 2,4-pyrimidinediaminecompounds and prodrugs of the invention are found in U.S. Pat. No.5,958,935, the disclosure of which is incorporated herein by reference.Specific examples describing the synthesis of numerous2,4-pyrimidinediamine compounds and prodrugs, as well as intermediatestherefore, are described in U.S. Pat. No. 7,060,827, the contents ofwhich are incorporated herein by reference. Suitable exemplary methodsthat can be routinely used and/or adapted to synthesize active2,4-pyrimidinediamine compounds can also be found in internationalapplication Serial No. PCT/US03/03022 filed Jan. 31, 2003 (WO03/063794), U.S. application Ser. No. 10/631,029 filed Jul. 29, 2003,international application Serial No. PCT/US03/24087 (WO2004/014382),U.S. application Ser. No. 10/903,263 filed Jul. 30, 2004, andinternational application Serial No. PCT/US2004/24716 (WO005/016893),the disclosures of which are incorporated herein by reference. All ofthe compounds described herein (including prodrugs) can be prepared byroutine adaptation of these methods.

Exemplary synthetic methods for the 2,4-substituted pyrimidinediaminesare described in U.S. Pat. No. 7,060,827 and U.S. Patent Publication No.2007-0203161 A1, incorporated herein by reference. Those of skill in theart will also be able to readily adapt these methods for the synthesisof specific 2,4-substituted pyrimidinediamines as described therein.Skilled artisans will recognize that in some instances certainsubstituents, such as, for example, R² and/or R⁴, may include functionalgroups requiring protection. The exact identity of the protecting groupused will depend upon, among other things, the identity of thefunctional group being protected and the reaction conditions used in theparticular synthetic scheme, and will be apparent to those of skill inthe art. Guidance for selecting protecting groups, their attachment andremoval suitable for a particular application can be found, for example,in Greene & Wuts, supra.

Prodrugs as described herein can be prepared by routine modification ofthe above-described methods. Alternatively, such prodrugs can beprepared by reacting a suitably protected 2,4-pyrimidinediamine 6 with asuitable progroup. Conditions for carrying out such reactions and fordeprotecting the product to yield a prodrugs as described herein arewell-known.

Myriad references teaching methods useful for synthesizing pyrimidinesgenerally, as well as starting materials described in Schemes (I)-(VII),are known in the art. For specific guidance, the reader is referred toBrown, D. J., “The Pyrimidines”, in The Chemistry of HeterocyclicCompounds, Volume 16 (Weissberger, A., Ed.), 1962, IntersciencePublishers, (A Division of John Wiley & Sons), New York (“Brown I”);Brown, D. J., “The Pyrimidines”, in The Chemistry of HeterocyclicCompounds, Volume 16, Supplement I (Weissberger, A. and Taylor, E. C.,Ed.), 1970, Wiley-Interscience, (A Division of John Wiley & Sons), NewYork (Brown II”); Brown, D. J., “The Pyrimidines”, in The Chemistry ofHeterocyclic Compounds, Volume 16, Supplement II (Weissberger, A. andTaylor, E. C., Ed.), 1985, An Interscience Publication (John Wiley &Sons), New York (“Brown III”); Brown, D. J., “The Pyrimidines” in TheChemistry of Heterocyclic Compounds, Volume 52 (Weissberger, A. andTaylor, E. C., Ed.), 1994, John Wiley & Sons, Inc., New York, pp. 1-1509(Brown IV”); Kenner, G. W. and Todd, A., in Heterocyclic Compounds,Volume 6, (Elderfield, R. C., Ed.), 1957, John Wiley, New York, Chapter7 (pyrimidines); Paquette, L. A., Principles of Modern HeterocyclicChemistry, 1968, W. A. Benjamin, Inc., New York, pp. 1-401 (uracilsynthesis pp. 313, 315; pyrimidinediamine synthesis pp. 313-316; aminopyrimidinediamine synthesis pp. 315); Joule, J. A., Mills, K. and Smith,G. F., Heterocyclic Chemistry, 3^(rd) Edition, 1995, Chapman and Hall,London, UK, pp. 1-516; Vorbrüggen, H. and Ruh-Pohlenz, C., Handbook ofNucleoside Synthesis, John Wiley & Sons, New York, 2001, pp. 1-631(protection of pyrimidines by acylation pp. 90-91; silylation ofpyrimidines pp. 91-93); Joule, J. A., Mills, K. and Smith, G. F.,Heterocyclic Chemistry, 4^(th) Edition, 2000, Blackwell Science, Ltd,Oxford, UK, pp. 1-589; and Comprehensive Organic Synthesis, Volumes 1-9(Trost, B. M. and Fleming, I., Ed.), 1991, Pergamon Press, Oxford, UK.

Those of skill in the art will appreciate that the 2,4-pyrimidinediaminecompounds described herein may include functional groups that can bemasked with progroups to create prodrugs. Such prodrugs are usually, butneed not be, pharmacologically inactive until converted into theiractive drug form. Indeed, many of the 2,4-pyrimidinediamine compoundsdescribed in this invention include promoieties that are hydrolyzable orotherwise cleavable under conditions of use. For example, ester groupscommonly undergo acid-catalyzed hydrolysis to yield the parentcarboxylic acid when exposed to the acidic conditions of the stomach, orbase-catalyzed hydrolysis when exposed to the basic conditions of theintestine or blood. Thus, when administered to a subject orally,2,4-pyrimidinediamine compounds that include ester moieties can beconsidered prodrugs of their corresponding carboxylic acid, regardlessof whether the ester form is pharmacologically active.

The mechanism by which the progroup(s) metabolizes is not critical, andcan be caused by, for example, hydrolysis under the acidic conditions ofthe stomach, as described above, and/or by enzymes present in thedigestive tract and/or tissues or organs of the body. Indeed, theprogroup(s) can be selected to metabolize at a particular site withinthe body. For example, many esters are cleaved under the acidicconditions found in the stomach. Prodrugs designed to cleave chemicallyin the stomach to the active 2,4-pyrimidinediamine can employ progroupsincluding such esters. Alternatively, the progroups can be designed tometabolize in the presence of enzymes such as esterases, amidases,lipolases, phosphatases including ATPases and kinase etc. Progroupsincluding linkages capable of metabolizing in vivo are well-known, andinclude, by way of example and not limitation, ethers, thioethers,silylethers, silylthioethers, esters, thioesters, carbonates,thiocarbonates, carbamates, thiocarbamates, ureas, thioureas,carboxamides, etc. In some instances, a “precursor” group that isoxidized by oxidative enzymes such as, for example, cytochrome P450 ofthe liver, to a metabolizable group, can be selected.

In the prodrugs, any available functional moiety can be masked with aprogroup to yield a prodrug. Functional groups within the2,4-pyrimidinediamine compounds that can be masked with progroups forinclusion in a promoiety include, but are not limited to, amines(primary and secondary), hydroxyls, sulfanyls (thiols), carboxyls, etc.Myriad progroups suitable for masking such functional groups to yieldpromoieties that are cleavable under the desired conditions of use areknown in the art. All of these progroups, alone or in combinations, canbe included in the prodrugs.

In some embodiments of the 2,4-pyrimidinediamine compounds and methodsof using the compounds, the progroup(s) can be attached to any availableprimary or secondary amine, including, for example, the N2 nitrogen atomof the 2,4-pyrimidinediamine moiety, the N4 nitrogen atom of the2,4-pyrimidinediamine moiety, and/or a primary or secondary nitrogenatom included in a substituent on the 2,4-pyrimidinediamine compound.

In particular embodiments of the 2,4-pyrimidinediamine compounds andmethods of using the compounds, the prodrugs described herein are2,4-pyrimidinediamine compounds that are substituted at the N4 nitrogenof the 2,4-pyrimidinediamine moiety with a substituted or unsubstitutednitrogen-containing bicyclic ring that includes at least one progroup atone or more of: the nitrogen atom(s) of the bicyclic ring, the N2nitrogen of the 2,4-pyrimidinediamine moiety and/or the N4 nitrogen ofthe 2,4-pyrimidinediamine moiety.

As noted above, the identity of the progroup is not critical, providedthat it can be metabolized under the desired conditions of use, forexample under the acidic conditions found in the stomach and/or byenzymes found in vivo, to yield a the biologically active group, e.g.,the 2,4-substituted pyrimidinediamines as described herein. Thus,skilled artisans will appreciate that the progroup can comprisevirtually any known or later-discovered hydroxyl, amine or thiolprotecting group. Non-limiting examples of suitable protecting groupscan be found, for example, in Protective Groups in Organic Synthesis,Greene & Wuts, 2nd Ed., John Wiley & Sons, New York, 1991 (especiallypages 10-142 (alcohols, 277-308 (thiols) and 309-405 (amines) thedisclosure of which is incorporated herein by reference).

Additionally, the identity of the progroup(s) can also be selected so asto impart the prodrug with desirable characteristics. For example,lipophilic groups can be used to decrease water solubility andhydrophilic groups can be used to increase water solubility. In thisway, prodrugs specifically tailored for selected modes of administrationcan be obtained. The progroup can also be designed to impart the prodrugwith other properties, such as, for example, improved passive intestinalabsorption, improved transport-mediated intestinal absorption,protection against fast metabolism (slow-release prodrugs),tissue-selective delivery, passive enrichment in target tissues,targeting-specific transporters, etc. Groups capable of impartingprodrugs with these characteristics are well-known, and are described,for example, in Ettmayer et al., 2004, J. Med. Chem. 47(10):2393-2404,the disclosure of which is incorporated by reference. All of the variousgroups described in these references can be utilized in the prodrugsdescribed herein.

In another embodiment, the present invention relates to a prostheticdevice suitable for use or implantation into a subject, preferably ahuman. The device is coated with a composition containing apyrimidinediamine of the invention. The device is preferably a stent.The formulated materials used in accordance with the present inventioncomprise a pyrimidinediamine having Syk inhibitory activity.

In such an embodiment, the compounds of the invention may be coated orsealed on a prosthetic device which is suitable, e.g., for implantationor other use in a subject, preferably a human. Examples of such devicesinclude, but are not limited to, all types of angioplasty devicesincluding a stent or stent/graft, or a commercial synthetic vasculargraft or a biologic vascular graft. Any stent, stent/graft or tissueengineered vascular graft (“tubes”) known in the art can be coated orsealed with the compounds of the present invention. The tubes can bemetallic, or made from a biocompatible polymer, as well as abiodegradable polymer, such as, e.g., dacron polyester, poly(ethyleneterephthalate), polycarbonate, polymethylmethacrylate, polypropylene,polyalkylene oxalates, polyvinylchloride, polyurethanes, polysiloxanes,nylons, poly(dimethyl siloxane), polycyanoacrylates, polyphosphazenes,poly(amino acids), ethylene glycol I dimethacrylate, poly(methylmethacrylate), poly(2-hydroxyethyl methacrylate), poly(HEMA),polyhydroxyalkanoates, polytetrafluorethylene, polycarbonate,poly(glycolide-lactide) co-polymer, polylactic acid,poly(.epsilon.-caprolactone), poly(.beta.-hydroxybutyrate),polydioxanone, poly(γ-ethyl glutamate), polyiminocarbonates, poly(orthoester), polyanhydrides, alginate, dextran, chitin, cotton, polyglycolicacid, polyurethane, or derivatized versions thereof, i.e., polymerswhich have been modified to include, for example, attachment sites orcross-linking groups in which the polymers retain their structuralintegrity while allowing for attachment of molecules, such as proteins,nucleic acids, and the like. The tubes can also be fabric-coated metalstructures. The tubes can also be made from combinations of metal andpolymer. The tubes can be configured into any desired shape orconformation, such as, for example, linear, tapered, bifurcated, etc.,and may be prepared using fiber technology, such as, e.g., crimped,woven, knitted, velour, double velour, with or without coils. The tubescan also be prepared by chemical extrusion, casting or molding using,for example, porous materials having linear or random pores that arecircular or geometric in shape.

There are a variety of methods of manufacture available to provide aprosthetic device, coated on at least one surface with a sufficientamount of a compound of the present invention. The resulting coating ispreferably uniform and should be integral so that contact between thedevice surface(s) and the surrounding tissue is precluded. The compoundscan be applied to the device by spraying at least one surface of thedevice with the compounds in suspension, and allowing the appliedsurface to dry. In another embodiment, the device can be dipped intosuch a suspension, or by casting a suspension of the compounds over thedevice, or by layering a device the a suspension of the compounds overthe device, or by impregnating a device with a suspension of thecompounds. The compounds may be applied to the inside surface of a tube.By applying the compounds on the inside of the tube, the compoundspromote proper reendothelialization of the lumen wall, promote woundhealing and prevent or inhibit one or more cardiovascular diseasestates, such as stenosis, restenosis or intimal and neointimalhyperplasias.

The particular amount of the preparation to be applied to the device canbe easily determined empirically by comparing devices with differentamounts of the compound coated thereon and determining the efficacy ofeach by, for example, measuring. Also, one skilled in the relevant artand who is familiar with standard treatments would also be in a positionto easily evaluate the efficacy of a device. Moreover, more than onecoat of the compounds, either untreated or crosslinked, can be appliedto a device. It is highly desirable to inspect the device once coated toinsure that there are no gaps or breaks present in the coating.

Other methods of coating stents are well known in the art and arecontemplated by the invention, for example, U.S. Pat. No. 5,637,113describes coating stents with a polymer film, U.S. Pat. No. 5,837,313describes a drug release stent coating process; both of these patentsare incorporated herein in their entireties and for all purposes.

In a specific embodiment, a stent coated with the compounds the presentinvention, is provided. The compounds in or on the stent may becomplexed with a drug, such as an antibiotic agent or an antiviralagent, or mixtures thereof, in order to insure against graft rejection.Additional drugs which may be added to the coating includeantiplatelets, antithrombins, cytostatic and antiproliferative agentsfor example.

The methods used for implanting the coated devices are analogous tothose used for the implantation of such devices without the coating,and, of course, depend on the nature of the condition to be modified orcorrected. The surgery can be performed under either local or systemicanesthesia and, generally, involves an incision, spacing to accommodatethe implant, insertion, and suture.

The invention having been described, the following examples are offeredby way of illustration and not limitation.

V. EXAMPLES A. Example 1 2,4-pyrimidinediamines Inhibit αIgM-InducedCD69 Expression in Primary B-Cells

Human BJAB B cells were routinely cultured in RPMI 1640 mediumsupplemented with 10% FCS (JRH Biosciences, Lenexa, Kans.), penicillin,and streptomycin. The BJAB cells were split to 2.5×10⁵ cells/ml 24-hoursbefore stimulation. Cells were spun and resuspended at 5×10⁵ cells/ml infresh complete RPMI 1640 medium in the presence of 5 or 10 μg/mlanti-IgM F(ab′)2 (Jackson ImmunoResearch, West Grove, Pa.), at 37° C.,and then assayed for surface CD69 expression. CD69 is a marker expressedy B cells activated via the B cell receptor (BCR). These activated cellsare the source of autoantibodies and of a wide variety of inflammatorycytokines believed to play a role in atherosclerosis (Physiol. Rev. 86:515-581 (2006)).

TABLE 1 EC50 [αIgM] Stimulation (μM) μg/mL Time (hrs) Donor 0.215 5 6 A0.195 5 6 B 0.239 10 6  C* n = 2 per data point; *primary B-cells wereobtained from AllCells.

B. Example 2 2,4-pyrimidinediamines Inhibit Mast Cell Activation Inducedby FcγR Cross-Linking

Human mast cells were cultured and differentiated from CD38-negativeprogenitor cell as described in U.S. Patent Publication No. 2005-234049,incorporated herein by reference. For example, 65 μl of variousconcentrations of 6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one(compound 1), prepared in MT (137 mM NaCl, 2.7 mM KCl, 1.8 mM CaCl₂, 1.0mM MgCl₂, 5.6 mM Glucose, 20 mM Hepes (pH 7.4), 0.1% Bovine SerumAlbumin, (Sigma A4503)) containing 2% MeOH and 1% DMSO, or controlbuffer were added to duplicate 96-well V-bottom plates. Pelleted andresuspended (in warm MT) CHMC cells (65 μl) were added to each 96-wellplate, mixed and incubated for 1 hr at 37° C. 25 μl of 6× anti-IgGRabbit anti-human IgG, Affinity purified (Bethyl Laboratories Cat No.A80-105A3) final concentration 1 μg/ml, was added to the test wells. MT(25 μl) was added to control wells. After a 60-minute incubation at 37°C., cells and cell debris were pelleted by centrifugation at 1000 rpmfor 10 min and tryptase and leukotriene C₄ levels were measured.

To measure tryptase levels, 25 μl of supernatant from each well wastransferred to a fresh 96-well black bottom plate, to which 100 μl offresh tryptase substrate solution [(Z-Ala-Lys-Arg-AMC2TFA; EnzymeSystems Products, #AMC-246)] 1:2000 in tryptase assay buffer [0.1 MHepes (pH 7.5), 10% w/v Glycerol, 10 μM Heparin (Sigma H-4898) 0.01%NaN₃] was added. After 30 min incubation at room temperature, theoptical density of the plates is measured at 355 nm/460 nm on aspectrophotometric plate reader. Table 2 provides the IC₅₀.

Leukotriene C4 (LTC4) levels were quantified using an ELISA kit onappropriately diluted supernatant samples following the supplier'sinstructions (Cayman Chemical Co., Cat No. 520211).

Inhibition of release and/or synthesis of lipid mediators was assessedby measuring the release of LTC4 and inhibition of release and/orsynthesis of cytokines was monitored by quantifying TNFα, IL-8, GM-CSF,IL-10 and IL-13. Cytokine (TNFα, IL-8, GM-CSF, IL-10, IL-13) productionwas measured 6-8 hrs post-IgG crosslinking. Leukotriene and cytokinelevels were quantified using the following commercial ELISA kits: LTC4(Cayman Chemical #520211), TNFα (Biosource #KHC3011), GM-CSF (Biosource#KHC0901), IL-10 (Biosource #KHC0122), and IL-13 (Biosource #KHC0132).

TABLE 2 EC₅₀ (μM) Com- Degranulation pound (tryptase) LTC4 TNFα IL-8GMCSF IL-10 IL-13 lot A 0.053 0.036 0.045 0.045 0.046 0.125 0.090 lot B0.076 0.047 0.120 0.062 0.067 0.148 0.148

C. Example 4 2,4-pyrimidinediamines Activate Platelets Via aSyk-Mediated Pathway

Human peripheral blood, from healthy volunteers who had not taken anymedication for at least 7 days, was drawn into Vacutainer-ACD tubes(Acid citrate dextrose (ACD) Solution Tubes, VWR Cat. No. VT4606).Platelet-rich plasma (PRP) and platelet-poor plasma (PPP) were preparedby differential centrifugation (200 g and >2500 g, respectively, 20 min,RT). Platelets in PRP were incubated for 10 min at 37° C. with testarticle-DMSO solutions that had been previously diluted in MT buffer(137 mM NaCl, 2.7 mM KCl, 1.8 mM CaCl₂, 1.0 mM MgCl₂, 5.6 mM glucose, 20mM Hepes, 0.1% BSA; pH 7.4). The test articles included dimethylSulfoxide (DMSO) (Sigma-Aldrich, Cat No. D2650), wortmannin Penicilliumfuniculosum (Sigma-Aldrich, Cat No. W1628), and6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one(compound 1).

Cells were stimulated with collagen (Chronolog Corp. Cat. No. 385) at 20μg/mL, adenosine 5′-diphosphate (ADP) (Sigma-Aldrich Cat. No. A2754) at33 μM, or phorbol 12-Myristate 13-Acetate (PMA) (Sigma-Aldrich Cat. No.P8139) at 33 ng/mL, for 15 min at 37° C., then incubated with stainingantibody (anti-CD62P PE) at RT in the dark for 20 min, and fixed withparaformaldehyde (Cytofix fixation buffer) in the dark for 30 min at RT.Finally, cells were washed with PBS containing 2% fetal bovine serum andstored at 4° C. in the dark prior to flow cytometry. Measurements wereperformed using a FACScalibur flow cytometer (BD Biosciences, San Jose,Calif., USA). CD62P expression was expressed as geometric meanfluorescence on the vertical axis. See FIG. 2.

Compound 1 inhibited collagen receptor mediated platelet activation.However, compound 1 did not inhibit CD62P surface upregulation inplatelets induced by ADP or PMA, confirming that compound 1 is actingupon platelets via a Syk-dependent pathway, i.e., collagen-mediatedsignaling.

1. A method of treating atherosclerosis or regressing or decreasingformation of arterial atherosclerotic lesions, said method comprisingadministering to a mammal having atherosclerosis an effective amount ofa Syk kinase inhibitor.
 2. The method of claim 1, wherein the Syk kinaseinhibitor is a compound of formula I:

wherein: L¹ and L² are each, independently of one another, selected fromthe group consisting of a direct bond and a linker; R² is selected fromthe group consisting of C₁₋₆ alkyl optionally substituted with one ormore of the same or different R⁸ groups, C₃₋₈ cycloalkyl optionallysubstituted with one or more of the same or different R⁸ groups, 3-8membered cycloheteroalkyl optionally substituted with one or more of thesame or different R⁸ groups, C₅₋₁₅ aryl optionally substituted with oneor more of the same or different R⁸ groups, and 5-15 membered heteroaryloptionally substituted with one or more of the same or different R⁸groups; R⁴ is selected from the group consisting of hydrogen, C₁₋₆ alkyloptionally substituted with one or more of the same or different R⁸groups, C₃₋₈ cycloalkyl optionally substituted with one or more of thesame or different R⁸ groups, 3-8 membered cycloheteroalkyl optionallysubstituted with one or more of the same or different R⁸ groups, C₅₋₁₅aryl optionally substituted with one or more of the same or different R⁸groups, and 5-15 membered heteroaryl optionally substituted with one ormore of the same or different R⁸ groups; R⁵ is selected from the groupconsisting of R⁶ and C₁₋₆ alkyl optionally substituted with one or moreof the same or different R⁸ groups; each R⁶ is independently selectedfrom the group consisting of hydrogen, —OR^(d), —SR^(d), C₁₋₃haloalkyloxy, C₁₋₃ perhaloalkyloxy, —NR^(c)R^(c), halogen, C₁₋₃haloalkyl, C₁₋₃ perhaloalkyl, —CN, —NC, —OCN, —SCN, —NO, —NO₂, —N₃,—S(O)R^(d), —S(O)₂R^(d), —S(O)₂OR^(d), —S(O)NR^(c)R^(c);—S(O)₂NR^(c)R^(c), —OS(O)R^(d), —OS(O)₂R^(c), —OS(O)₂OR^(d),—OS(O)NR^(c)R^(c), —OS(O)₂NR^(c)R^(c), —C(O)R^(d), —C(O)OR^(d),—C(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c), —OC(O)R^(d), —SC(O)R^(d),—OC(O)OR^(d), —SC(O)OR^(d), —OC(O)NR^(c)R^(c), —SC(O)NR^(c)R^(c),—OC(NH)NR^(c)R^(c), —SC(NH)NR^(c)R^(c), —[NHC(O)]_(n)R^(d)—,—[NHC(O)]_(n)OR^(d), —[NHC(O)]_(n)NR^(c)R^(c) and—[NHC(NH)]_(n)NR^(c)R^(c), C₆₋₁₀ aryl optionally substituted with one ormore of the same or different R⁸ groups, C₆₋₁₆ arylalkyl optionallysubstituted with one or more of the same or different R⁸ groups, 5-10membered heteroaryl optionally substituted with one or more of the sameor different R⁸ groups and 6-16 membered heteroarylalkyl optionallysubstituted with one or more of the same or different R⁸ groups; R⁸ isselected from the group consisting of R^(e), R^(b), R^(e) substitutedwith one or more of the same or different R^(a) or R^(b), —OR^(a)substituted with one or more of the same or different R^(a) or R^(b),—B(OR^(a))₂, —B(NR^(c)R^(c))₂, —(CH₂)_(m)—R^(b), —(CHR^(a))_(m)—R^(b),—O—(CH₂)_(m)—R^(b), S(CH₂)_(m)—R^(b), —O—CHR^(a)R^(b),—O—CR^(a)(R^(a))₂, —O—(CHR^(a))_(m)—R^(b),—O—(CH₂)_(m)—CH[(CH₂)_(m)R^(b)]R^(b), —S—(CHR^(a))_(m)—R^(b);—C(O)NH—(CH₂)_(m)—R^(b), —C(O)NH—(CHR^(a))_(m)—R^(b),—O(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b), —S—(CH₂)_(m)—R^(b),—C(O)NH—(CH₂)_(m)R^(b), —O—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b),—S—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b), —NH—(CH₂)_(m)—R^(b),—NH—(CHR^(a))_(m)—R^(b), —NH[(CH₂)_(m)R^(b)], —N[(CH₂)_(m)R^(b)]₂,—NH—C(O)—NH—(CH₂)_(m)—R^(b), —NH—C(O)—(CH₂)_(m)—CHR^(b)R^(b) and—NH—(CH₂)_(m)—C(O)—NH—(CH₂)_(m)—R^(b); each R^(a) is independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, C₃₋₈cycloalkyl, C₄₋₁₁ cycloalkylalkyl, C₅₋₁₀ aryl, C₆₋₁₆ arylalkyl, 2-6membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 memberedcycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 memberedheteroarylalkyl; each R^(b) is independently selected from the groupconsisting of ═O, —OR^(d), (C1-C3) haloalkyloxy, ═S, —SR^(d), ═NR^(d),═NOR^(d), —NR^(c)R^(c), halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂,═N₂, —N₃, —S(O)R^(d), —S(O)₂R^(d), —S(O)₂OR^(d), —S(O)NR^(c)R^(c),—S(O)₂NR^(c)R^(c), —OS(O)R^(d), —OS(O)₂R^(d), —OS(O)₂OR^(d),—OS(O)₂NR^(c)R^(c), —C(O)R^(d), —C(O)OR^(d), —C(O)NR^(c)R^(c),—C(NH)NR^(c)R^(c), —C(NR^(a))NR^(c)R^(c), —C(NOH)R^(a),—C(NOH)NR^(c)R^(c), —OC(O)R^(d), —OC(O)OR^(d), —OC(O)NR^(c)R^(c),—OC(NH)NR^(c)R^(c), —OC(NR^(a))NR^(c)R^(c), —[NHC(O)]_(n)R^(d),—[NR^(a)C(O)]_(n)R^(d), —[NHC(O)]_(n)OR^(d), —[NR^(a)C(O)]_(n)OR^(d),—[NHC(O)]_(n)NR^(c)R^(c), —[NR^(a)C(O)]_(n)NR^(c)R^(c),—[NHC(NH)]_(n)NR^(c)R^(c) and —[NR^(a)C(NR^(a))]_(n)NR^(c)R^(c); eachR^(c) is independently a protecting group or R^(a), or, alternatively,each R^(c) is taken together with the nitrogen atom to which it isbonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl whichmay optionally include one or more of the same or different additionalheteroatoms and which may optionally be substituted with one or more ofthe same or different R^(a) or R^(b) groups; each R^(d) is independentlya protecting group or R^(a); each R^(e) is independently selected fromthe group consisting of C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₅₋₁₀ aryl, C₆₋₁₆ arylalkyl, 2-6 membered heteroalkyl,3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10membered heteroaryl and 6-16 membered heteroarylalkyl; each m isindependently an integer from 1 to 3; and each n is independently aninteger from 0 to
 3. 3. The method of claim 2, wherein R⁶ is hydrogenand each of L¹ and L² is a direct bond.
 4. The method of claim 3,wherein R⁵ is selected from the group consisting of halo, —CN, —NO₂,—C(O)R^(a), —C(O)OR^(a), —C(O)CF₃, —C(O)OCF₃, C₁₋₃ haloalkyl, C₁₋₃perhaloalkyl, C₁₋₃ haloalkoxy, and C₁₋₃ perhaloalkoxy.
 5. The method ofclaim 4, wherein R⁵ is fluoro.
 6. The method of claim 3, wherein R² isselected from the group consisting of phenyl, naphthyl, and 5-10membered heteroaryl, optionally substituted with one or more of the sameor different R⁸ groups.
 7. The method of claim 3, wherein R² is selectedfrom the group consisting of benzodioxanyl, 1,4-benzodioxan-(5 or 6)-yl,benzodioxolyl, 1,3-benzodioxol-(4 or 5)-yl, benzoxazinyl,1,4-benzoxazin-(5, 6, 7 or 8)-yl, benzoxazolyl, 1,3-benzoxazol-(4, 5, 6or 7)-yl, benzopyranyl, benzopyran-(5, 6, 7 or 8)-yl, benzotriazolyl,benzotrazol-(4, 5, 6 or 7)-yl, 1,4-benzoxazinyl-2-one,1,4-benzoxazin-(5, 6, 7 or 8)-yl-2-one, 2H-1,4-benzoxazinyl-3(4H)-one,2H-1,4-benzoxazin-(5, 6, 7 or 8)-yl-3(4H)-one,2H-1,3-benzoxazinyl-2,4(3H)-dione, 2H-1,3-benzoxazin-(5, 6, 7 or8)-yl-2,4(3H)-dione, benzoxazolyl-2-one, benzoxazol-(4, 5, 6 or7)-yl-2-one, dihydrocoumarinyl, dihydrocoumarin-(5, 6, 7 or 8)-yl,1,2-benzopyronyl, 1,2-benzopyron-(5, 6, 7 or 8)-yl, benzofuranyl,benzofuran-(4, 5, 6 or 7)-yl, benzo[b]furanyl, benzo[b]furan-(4, 5, 6,or -7)-yl, indolyl, indol-(4, 5, 6 or 7)-yl, pyrrolyl and pyrrol-(1 or2)-yl, optionally substituted with one or more of the same of differentR⁸ groups.
 8. The method of claim 3, wherein one or both of R² and R⁴are, independently of one another, a heteroaryl selected from the groupconsisting of:

wherein: p is an integer from one to three; each - - - independentlyrepresents a single bond or a double bond; R³⁵ is hydrogen or R⁸; X isselected from the group consisting of CH, N and N—O; each Y isindependently selected from the group consisting of O, S and NH; each Y¹is independently selected from the group consisting of O, S, SO, SO₂,SONR³⁶, NH and NR³⁷; each Y² is independently selected from the groupconsisting of CH, CH₂, O, S, N, NH and NR³⁷; R³⁶ is hydrogen or alkyl;R³⁷ is selected from the group consisting of hydrogen and a progroup,R³⁸ is selected from the group consisting of alkyl and aryl; A isselected from the group consisting of O, NH and NR³⁸; R⁹, R¹⁰, R¹¹ andR¹² are each, independently of one another, selected from the groupconsisting of alkyl, alkoxy, halogen, haloalkoxy, aminoalkyl andhydroxyalkyl, or, alternatively, R⁹ and R¹⁰ or R¹¹ and R¹², or R⁹ andR¹⁰ and R¹¹ and R¹² are taken together form an oxo group; each Z isselected from the group consisting of hydroxyl, alkoxy, aryloxy, ester,and carbamate; Q is selected from the group consisting of —OH, OR⁸,—NR^(c)R^(c), —NHR³⁹—C(O)R⁸, —NHR³⁹—C(O)OR⁸, —NR³⁹—CHR⁴⁰—R^(b),—NR³⁹—(CH₂)_(m)—R^(b) and —NR³⁹—C(O)—CHR⁴⁰—NR^(c)R^(c); and R³⁹ and R⁴⁰are each, independently of one another, selected from the groupconsisting of hydrogen, alkyl, aryl, alkylaryl, arylalkyl and NHR⁸. 9.The method of claim 8, wherein R² is phenyl substituted with one or moreR⁸ groups.
 10. The method of claim 9, wherein R² is phenyl substitutedwith one to three alkoxy groups.
 11. The method of claim 8, wherein R⁴is


12. A method of treating atherosclerosis or regressing or decreasingformation of arterial atherosclerotic lesions, said method comprisingadministering to a mammal having atherosclerosis an effective amount ofa compound of formula III:

wherein each of R² and R⁴ independently is phenyl substituted with oneor more R⁸ groups or a heteroaryl selected from the group consisting of

wherein: R³⁵ is hydrogen or R⁸; R⁸ is R^(e), R^(b), R^(e) substitutedwith one or more of the same or different R^(a) or R^(b), —OR^(a)substituted with one or more of the same or different R^(a) or R^(b),—B(OR^(a))₂, —B(NR^(c)R^(c))₂, —(CH₂)_(m)—R^(b), —(CHR^(a))_(m)—R^(b),—O—(CH₂)_(m)—R^(b), —S—(CH₂)_(m)—R^(b), —O—CHR^(a)R^(b),—O—CR^(a)(R^(b))₂, —O—(CHR^(a))_(m)—R^(b),—O—(CH₂)_(m)—CH[(CH₂)_(m)R^(b)]R^(b), —S—(CHR^(a))_(m)—R^(b),—C(O)NH—(CH₂)_(m)—R^(b), —C(O)NH—(CHR^(a))_(m)—R^(b),—O—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),—S—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),—O—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b),—S—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b), —NH—(CH₂)_(m)—R^(b),—NH—(CHR^(a))_(m)—R^(b), —NH[(CH₂)_(m)R^(b)], —NH[(CH₂)_(m)R^(b)]₂,—NH—C(O)—NH—(CH₂)_(m)—R^(b), —NH—C(O)—(CH₂)_(m)—CHR^(b)R^(b) or—NH—(CH₂)_(m)—C(O)—NH—(CH₂)_(m)—R^(b); each R^(a) is independentlyselected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8)cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) arylalkyl,2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 memberedcycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 memberedheteroarylalkyl; each R^(b) is independently selected from the groupconsisting of ═O, —OR^(d), (C1-C3) haloalkyloxy, ═S, —SR^(d), ═NR^(d),═NOR^(d), —NR^(c)R^(c), halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂,═N₂, —N₃, —S(O)R^(d), —S(O)₂R^(d), —S(O)₂OR^(d), —S(O)NR^(c)R^(c),—S(O)₂NR^(c)R^(c), —OS(O)R^(d), —OS(O)₂R^(d), —OS(O)₂OR^(d),—OS(O)₂NR^(c)R^(c), —C(O)R^(d), —C(O)OR^(d), —C(O)NR^(c)R^(c),—C(NH)NR^(c)R^(c), —C(NR^(a))NR^(c)R^(c), —C(NOH)R^(a),—C(NOH)NR^(c)R^(c), —OC(O)R^(d), —OC(O)OR^(d), —OC(O)NR^(c)R^(c),—OC(NH)NR^(c)R^(c), —OC(NR^(a))NR^(c)R^(c), —[NHC(O)]_(n)R^(d),—[NR^(a)C(O)]_(n)R^(d), —[NHC(O)]_(n)OR^(d), —[NR^(a)C(O)]_(n)OR^(d),—[NHC(O)]₁₇NR^(c)R^(c), —[NR^(a)C(O)]_(n)NR^(c)R^(c),—[NHC(NH)]_(n)NR^(c)R^(c) and —[NR^(a)C(NR^(a))]_(n)NR^(c)R^(c); eachR^(c) is independently a protecting group or R^(a), or, alternatively,two R^(c) are taken together with the nitrogen atom to which they arebonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl whichmay optionally include one or more of the same or different additionalheteroatoms and which may optionally be substituted with one or more ofthe same or different R^(a) or R^(b) groups; each R^(d) is independentlya protecting group or R^(a); each R^(e) is independently selected fromthe group consisting of (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl,(C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) arylalkyl, 2-6membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 memberedcycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 memberedheteroarylalkyl; X is selected from the group consisting of CH, N andN—O; each Y independently is selected from the group consisting of O, Sand NH; each Y¹ independently is selected from the group consisting ofO, S, SO, SO₂, SONR³⁶, NH and NR³⁵; each Y² independently is selectedfrom the group consisting of CH, CH₂, O, S, N, NH and NR³⁵; each R³⁶independently is hydrogen or alkyl; A is selected from the groupconsisting of O, NH and NR³⁸; Q is selected from the group consisting of—OH, OR⁸, —NR^(c)R^(c), NHR³⁹C(O)R⁸, —NHR³⁹—C(O)OR⁸, —NR³⁹—CHR⁴⁰—R^(b),—NR³⁹—(CH₂)_(m)—R^(b) and —NR³⁹—C(O)—CHR⁴⁰—NR^(c)R^(c); each R³⁸independently is selected from the group consisting of alkyl and aryl;R⁹, R¹⁰, R¹¹ and R¹² are each, independently of one another, selectedfrom the group consisting of alkyl, alkoxy, halogen, haloalkoxy,aminoalkyl and hydroxyalkyl, or, alternatively, R⁹ and R¹⁰ or R¹¹ andR¹², or R⁹ and R¹⁰ and R¹¹ and R¹² are taken together form an oxo group;each Z is selected from the group consisting of hydroxyl, alkoxy,aryloxy, ester, and carbamate; Q is selected from the group consistingof —OH, OR⁸, —NR^(c)R^(c), —NHR³⁹—C(O)R⁹, —NHR³⁹—C(O)OR⁸,—NR³⁹—CHR⁴⁰—R^(b), —NR³⁹—(CH₂)_(m)—R^(b) and—NR³⁹—C(O)—CHR⁴⁰—NR^(c)R^(c); and R³⁹ and R⁴⁰ are each, independently ofone another, selected from the group consisting of hydrogen, alkyl,aryl, alkylaryl, arylalkyl and NHR⁸; and each m independently is aninteger from 1 to 3; and each n is independently an integer from 0 to 3.13. A method of treating atherosclerosis or regressing or decreasingformation of arterial atherosclerotic lesions, said method comprisingadministering to a mammal having atherosclerosis an effective amount ofa compound of formula II:

wherein: Y is selected from the group consisting of CH₂, NR²⁴, O, S,S(O) and S(O)₂; Z¹ and Z² each, independently of one another, areselected from the group consisting of CH and N; R² is selected from thegroup consisting of (CI-C6) alkyl optionally substituted with one ormore of the same or different R⁸ groups, (C3-C8) cycloalkyl optionallysubstituted with one or more of the same or different R⁸ groups, 3-8membered cycloheteroalkyl optionally substituted with one or more of thesame or different R⁸ groups, (C6-C14) aryl optionally substituted withone or more of the same or different R⁸ groups, and 5-15 memberedheteroaryl optionally substituted with one or more of the same ordifferent R⁸ groups; R⁵ is selected from the group consisting of halo,cyano, nitro, and trihalomethyl; R⁸ is selected from the groupconsisting of R^(a), R^(b), R^(a) substituted with one or more of thesame or different R^(a) or R^(b), —OR^(a) substituted with one or moreof the same or different R^(a) or R^(b), —B(OR^(a))₂, —B(NR^(c)R^(c))₂,—(CH₂)_(m)—R^(b), —(CHR^(a))_(m)—R^(b), —O—(CH₂)_(m)—R^(b),—S—(CH2)_(m)—R^(b), —O—CHR^(a)R^(b), —O—CR^(a)(R^(b))₂,—O—(CHR^(a))_(m)—R^(b), —O—(CH₂)_(m)—CH [(CH₂)_(m)R^(b)]R^(b),—S—(CHR^(a))_(m)—R^(b), —C(O)NH—(CH₂)_(m)—R^(b),—C(O)NH—(CHR^(a))_(m)—Rb, —O—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b)—S—(CH₂)_(m)—C(O)NH—(CH2)_(m)—R^(b),—O—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b),—S—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b), —NH—(CH₂)_(m)—R^(b),—NH—(CHR^(a))_(m)—R^(b), —NH[(CH₂)_(m)R^(b)], —N[(CH₂)_(m)R^(b)]₂,—NH—C(O)—NH—(CH₂)_(m)—R^(b), —NH—C(O)—(CH₂)_(m)—CHR^(b)R^(b) and—NH—(CH₂)_(m)—C(O)—NH—(CH₂)_(m)—R^(b); R¹⁷ is selected from the groupconsisting of hydrogen, halogen, and lower alkyl or, alternatively, R¹⁷may be taken together with R¹⁸ to form an oxo (═O) group or, togetherwith the carbon atom to which they are attached, a spirocycle containingfrom 3 to 7 carbon atoms; R¹⁸ is selected from the group consisting ofhydrogen, halogen, and lower alkyl or, alternatively, R¹⁸ may be takentogether with R¹⁷ to form an oxo (═O) group or, together with the carbonatom to which they are attached, a spirocycle containing from 3 to 7carbon atoms; R¹⁹ is selected from the group consisting of hydrogen andlower alkyl or, alternatively, R¹⁹ may be taken together with R²⁰ toform an oxo (═O) group or, together with the carbon atom to which theyare attached, a spirocycle containing from 3 to 7 carbon atoms; R²⁰ isselected from the group consisting of hydrogen and lower alkyl or,alternatively, R²⁰ may be taken together with R¹⁹ to form an oxo (═O)group or, together with the carbon atom to which they are attached, aspirocycle containing from 3 to 7 carbon atoms; each R^(a) is,independently of the others, selected from hydrogen, lower alkyl, lowercycloalkyl, (C4-C11) cycloalkylalkyl, (C6-C10) aryl, (C7-C16) arylalkyl,2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 memberedcycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 memberedheteroarylalkyl; each R^(b) is independently selected from ═O, —OR^(a),(C1-C3) haloalkyloxy, ═S, —SR^(a), ═NR^(a), ═NOR^(a), —NR^(c)R^(c),halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(a),—S(O)₂R^(a), —S(O)₂OR^(a), —S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c),—OS(O)R^(a), —OS(O)₂R^(a), —OS(O)₂OR^(a), —OS(O)₂NR^(c)R^(c),—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c),—C(NR^(a))NR^(c)Rc, —C(NOH)R^(a), —C(NOH)NR^(c)R^(c), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(c)R^(c), —OC(NH)NR^(c)R^(c),—OC(NR^(a))NR^(c)R^(c), —[NHC(O)]_(n)R^(a), —[NR^(a)C(O)]_(n)R^(a),—[NHC(O)]_(n)OR^(a), —[NR^(a)C(O)]_(n)OR^(a), —[NHC(O)]_(n)NR^(c)R^(c),—[NR^(a)C(O)]_(n)NR^(c)R^(c), —[NHC(NH)]_(n)NR^(c)R^(c) and—[NR^(a)C(NR^(a))]_(n)NR^(c)R^(c); each R^(c) is, independently of theothers, selected from the group consisting of a protecting group andR^(a), or, alternatively, the two R^(c) bonded to the same nitrogen atomare taken together with that nitrogen atom to form a 5 to 8-memberedcycloheteroalkyl or heteroaryl which may optionally include one or moreof the same or different additional heteroatoms and which may optionallybe substituted with one or more of the same or different R^(a) groups;R²¹, R²² and R²³ are each, independently of one another, selected fromthe group consisting of hydrogen and a progroup R^(P); R^(P) has theformula —(CR^(d)R^(d))_(y)-A-R³, where y is an integer ranging from 1 to3; A is O or S; each R^(d) is, independently of the others, selectedfrom the group consisting of hydrogen, optionally substituted loweralkyl, optionally substituted (C6-C14) aryl and optionally substituted(C7-C20) arylalkyl; where the optional substituents are, independentlyof one another, selected from hydroxyl, lower alkoxy, (C6-C14) aryloxy,lower alkoxyalkyl and halogen, or, alternatively, two R^(d) bonded tothe same carbon atom, taken together with the carbon atom to which theyare bonded, form a cycloalkyl group containing from 3 to 8 carbon atoms;R³ comprises, together with the heteroatom, A, to which it is bonded, analcohol, an ether, a thioether, a silyl ether, a silyl thioether, anester, a thioester, an amide, a carbonate, a thiocarbonate, a carbamate,a thiocarbamate, a urea, a phosphate, a phosphate salt or a phosphateester; each m is, independently of the others, an integer from 1 to 3;and each n is, independently of the others, an integer from 0 to 3, withthe proviso that at least one of R²¹, R²², and R²³ is R^(P).
 14. Themethod of claim 12, wherein the compound isN4-(2,2-dimethyl-4-[(dihydrogenphosphonoxy)methyl]-3-oxo-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamineor a salt thereof.
 15. The method of claim 1 wherein the Syk kinaseinhibitor has an IC₅₀ of 20 μM or lower.